Surfactant-free water-free foamable compositions, breakable foams and gels and their uses

ABSTRACT

A substantially surface active agent free composition which includes a hydrophobic solvent, and/or a petrolatum, a paraffin wax and/or a fatty alcohol, a fatty acid and/or a wax and/or shea butter, with and without a propellant. A substantially surface active agent free composition, further comprising, a tetracycline antibiotic, or a vitamin D derivative, or one or more other active agents. A method of treatment using a substantially surface active agent free composition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/850,655, filed Sep. 10, 2015, which is a continuation of U.S.application Ser. No. 14/577,659, filed Dec. 19, 2014, which is acontinuation of U.S. application Ser. No. 13/499,501, which is a U.S.National Stage entry under 35 U.S.C. § 371 of International ApplicationNo. PCT/IB2010/002612, filed Oct. 1, 2010, which claims the benefit ofpriority under 35 U.S.C. § 119(e) to U.S. Provision al Application No.61/248,144 filed Oct. 2, 2009 and entitled “Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams and Their Uses”; U.S. ProvisionalApplication No. 61/322,148 filed Apr. 8, 2010 and entitled“Surfactant-Free Water-Free Foamable Compositions, Breakable Foams andTheir Uses”; U.S. Provisional Application No. 61/349,911 filed May 31,2010 and entitled “Surfactant-Free Water-Free Foamable Compositions,Breakable foams and Their Uses”; U.S. Provisional Application No.61/385,385 filed Sep. 22, 2010 and entitled “′Surfactant-Free Water-FreeFoamable Compositions, Breakable Foams and Gels and Their Uses”; U.S.Provisional Application No. 61/331,126 filed May 4, 2010 and entitled“Compositions, Gels and Foams with Rheology Modulators and UsesThereof”; and U.S. Provisional Application No. 61/380,568 filed Sep. 7,2010 and entitled “Surfactant-Free Water-Free Foamable Compositions andBreakable Foams and Their Uses”; all of which are herein incorporated intheir entirety by reference.

BACKGROUND

Foam compositions with high amounts of hydrophobic solvents are littleknown in the art.

Foams and, in particular, oleaginous single-phase foams are complicatedsystems which do not form under all circumstances. Slight shifts in foamcomposition, such as by the addition of active ingredients or theremoval of any of the essential ingredients, may destabilize the foam.

The prior art teaches oleaginous foam compositions require significantamounts of surface active agents to form, a foam. These compositionsrequire various standard surfactants, as essential components.

Surfactants are known as essential ingredients in foam, compositionsbecause of their amphiphilic properties and because they are consideredessential in forming a foam. However, many surfactants are known to beirritating when left on the skin, as they can extract lipids from theskin, thereby damaging skin barrier and exposing the skin to contactwith pro-inflammatory factors. (See for example: Effendy, I. andMaibach, H. I. “Surfactants and Experimental Irritant ContactDermatitis.” Contact Dermatol., 33 (1995), 217-225). Many surfactantscan also react with unstable active agents and lead to their rapiddegradation.

Briefly, the term surfactant has been often loosely used in the art toinclude substances which do not function effectively as stand alonesurfactants to reduce surface tension between two substances or phases.Reduction of surface tension can be significant in foam technology inrelation to the ability to create small stable bubbles. In the contextherein, the term “standard surfactant” or “customary surfactant” refersto customary non-ionic, anionic, cationic, zwitterionic, amphoteric andamphiphilic surfactants. Many standard surfactants are derivatives offatty alcohols or fatty acids, such as ethers or esters formed from suchfatty alcohols or fatty acids with hydrophilic moieties, such aspolyethyleneglycol (PEG). However, a native (non derivatized) fattyalcohol or fatty acid, as well as waxes are not regarded as a standardsurfactant.

In the context herein the term “foam adjuvant” includes only nativefatty alcohols and fatty acids. These are amphiphatic, and essentiallyhydrophobic with a minor hydrophilic region. For the purposes of formingan emulsion these foam adjuvants, unlike “standard” or “customarysurfactants”, are not effective as stand-alone surfactants in foamableemulsion compositions, because of their very weak emulsifying capacityon their own. Fatty alcohols and fatty acids have been loosely describedas co-surfactants in foamable emulsion compositions, because they assistcustomary surfactants to boost foam quality, help evolve the foamingproperties and because they stabilize the foam in part because of theirproperty as thickeners.

SUMMARY

The present application relates to oleaginous foamable formulations andfoams and their uses comprising hydrophobic solvents. In addition, itrelates to formulations with an active agent. Surprisingly, theapplication also relates to foamable formulations and foam withoutsurfactants; and/or without surfactants and polymeric agents. In one ormore embodiments the hydrophobic solvents are provided as part of a drugcarrier. For example certain drugs require hydrophobic solvents in orderto solubilize them. In one or more other embodiments, the hydrophobicsolvents are provided to facilitate or enhance the transdermalpenetration or delivery of a drug. In one or more additional cases, thehydrophobic sol vents are provided to have an occlusive effect at thetarget site, for example where the site of treatment is a damaged skinand the occlusive effect of hydrophobic solvents is desirable. Theapplication further describes semi solid gel compositions that liquefyoil application of mild shear force such as gentle rubbing.

It is known in the art that foams can easily be formulated based on highamounts of water, in combination with surface active agents, foamadjuvants and polymeric agents. As described in the literature,hydrophobic solvents can have a de-foaming effect which makes theformulation of foams based on hydrophobic solvents challenging,especially in compositions that do not contain water. To overcome thischallenge, the prior art requires the use of substantial levels ofsurfactants that act as foaming agents. Surface active agents are knownto be irritating, especially ionic surface active agents and repeateduse can cause dry skin and so it is desirable to reduce their use inpharmaceutical compositions intended to treat skin or mucosa. The priorart further teaches the incorporation of foam adjuvants, such as fattyalcohols and fatty acids, as foam stabilizing agents and also theincorporation of polymeric agents (e.g. gelling agents) as foamstabilizers, which can prolong the collapse time of a foam. Waxes mayalso be introduced into these surfactant-based formulations but as willbe appreciated, waxes, which are solids at ambient temperature, caneasily precipitate.

The technical problems to be overcome in formulating carriers andpharmaceutical compositions with hydrophobic solvent (a) withoutsurfactants; and/or (b) without polymeric agents and/or (c) withoutwater and/or (e) without short chain alcohols and/or (f) withoutpolyols; are multifold and include finding a suitable substitute forsurfactant which provides foam generating properties; finding a suitablereplacement that preferably does not need to have a foam adjuvantpresent with the surfactant (substitute), which if present would interalia help to boost the foam and as an aid to the surfactant andpreferably does not need to have a polymeric agent present with thesurfactant (substitute), which if present would inter alia help prolongstability of the foam.

It was surprisingly discovered in the present invention, that surfaceactive agents can be advantageously eliminated and replaced by foamadjuvants and waxes in the context of hydrophobic solvent based-foams.Waxes possess several advantages over other foaming agents such asexcellent skin compatibility, almost no chemical reactivity whichensures active ingredients stability and efficient skin occlusion whichhelps reducing skin water loss and can enhance skin penetration ofactive agents. Albeit waxes introduce their own additional problems intoformulating foamable compositions and foams, including their tendency tosolidify and precipitate out from a formulation and to block canistervalves, against which the formulations need to be designed so that theformulations are not negatively disturbed upon adding an effectiveamount of propellant and that the formulations are shakable and arehomogenous and can readily reform at least upon mild or reasonableshaking prior to use.

Incorporated in or added to the above is the aspect of how to provideformulations in which unstable active ingredients, such astetracyclines, which readily degrade can nevertheless remainsufficiently chemically stable for prolonged periods of time such thatallowing for a reasonable or acceptable amount of breakdown (for exampleas may be accepted by a regulatory drug authority) they remain capableof providing a therapeutic effect or prevention or remission of adisorder or disease (hereinafter “chemically stable”). A furtherchallenge is providing and delivering a composition in which the activeagent is homogenous. Additionally the formulations should avoid the useof substances, which can be irritating if applied to a sensitive targetor can cause depletion or drying or soreness on repeated use.

Incorporated in or added to the above is the aspect of how to providephysically stable formulations which are at least short term stable uponrelease from the pressurized container and not break as a result ofexposure to skin temperature. Foams which are structurally stable on theskin for at least one minute are termed “short term stable” carriers orfoams. In another aspect of physically stability the foamableformulation including propellant remains homogenous and does notseparate to any significant extent for at least one minute after beingshaken (hereinafter “physically stable”).

A feature of a product for cosmetic or medical use is long termstability. Propellants, which are a mixture of low molecular weighthydrocarbons, tend to impair the stability. The foamable compositionsherein are surprisingly stable, even in the absence of customarysurfactants. Following accelerated stability studies, they demonstratedesirable texture; they form fine bubble structures that do not breakimmediately upon contact with a surface, spread easily on the treatedarea and absorb quickly. In one or more embodiments the foam compositionhas an acceptable shelf-life of at least six months. In one or moreembodiments the foam composition has an acceptable shelf-life of atleast one year. In one or more embodiments the foam composition has anacceptable shelf-life of at least 15 months, or at least 18 months or atleast 21 months or at least two years at ambient temperature.

In one or more embodiments there is provided a composition which is asingle phase.

In one or more embodiments there is provided a composition whichprevents the degradation of the active ingredient upon application onthe target site of treatment.

Thanks to the absence of surfactants in the compositions, the oleaginousformulations and foams of the present invention, containing differentconcentrations of minocycline hydrochloride, demonstrated no signs ofirritation as demonstrated using an in vitro irritation HET-CAM test. Inone or more embodiments the drug carrier is formulated for use onsensitive targets such as the eye. In one or more embodiments the activepharmaceutical ingredients are formulated for use on sensitive targetareas such as sensitive or damaged skin areas, wounds, burns, mucosalmembranes, and body cavities. Hydrophobic solvents that are suitable,for example, for eye treatment or for use in wounds or burns. In one ormore embodiments the drug carrier and the respective pharmaceuticalcomposition with an active agent are both formulated for use onsensitive targets such as the eye. In one or more embodiments thecomposition is intended for use in treatment or prevention of eyeinfections.

Unexpectedly, it has been discovered that quality oleaginousformulations and foams can be achieved without the presence ofsignificant amounts of standard surfactants. Thus, in one or moreembodiments, there is provided a substantially surfactant freeoleaginous formulation or foam. In one or more embodiments, there isprovided an essentially surfactant free oleaginous formulation or foam.In one or more preferred embodiments the oleaginous formulations andfoams are free of surfactants. Further, unexpectedly, it has beendiscovered that quality oleaginous formulations and foams can beachieved without the presence of significant amounts of standardpolymeric agents (e.g. gelling agents). Thus, in one or moreembodiments, there is provided a substantially surfactant-free andsubstantially polymeric agent-free oleaginous formulation or foam. Inone or more preferred embodiments the oleaginous formulations and foamsare free of standard surfactants and polymers. Moreover, it has beenfurther discovered that these formulations and foams can be achievedover a large range of hydrophobic solvent content. There is thusprovided easy to use, chemically and physically stable andnon-irritating topical foam formulations, and pharmaceuticalcompositions thereof, containing a stable or stabilized activepharmaceutical or cosmetic agent having a therapeutic or beneficialeffect, intended for treatment of dermal and mucosal tissues free orsubstantially free of standard surfactants and/or polymeric agents.

In one or more embodiments there is provided a safe and effectivefoamable carrier composition and foam comprising a hydrophobic solvent,an oleaginous foamer complex (also termed “foamer complex”), comprisinga first member, comprising about 0.1% to about 20% by weight of a fattyalcohol; and a second member, comprising about 0.1% to about 20% byweight of (i) a fatty acid; and/or (ii) a wax; and a liquefied orcompressed gas propellant. In one or more embodiments the foamer agentcomprises a paraffin wax alone or in combination with the first memberand/or the second member. In certain embodiments, the concentration ofthe propellant is about 3% to about 30% by w eight of the totalcomposition.

In other certain embodiments, the concentration of the propellant isabout 1% to about 3% by weight of the total composition; or about 3% toabout 25%; or about 7% to about 17%; or about 10% to about 14%. Where abag in can or can in can system is used where part of the propellant isin the formulation and part separate from the formulation, the amount inthe formulation may be as little as about 1% by weight of the totalcomposition. In additional embodiments there is provided a safe andeffective foamable pharmaceutical or cosmetic composition and foamcomprising at least one active agent. In additional embodiments there isprovided a safe and effective foamable pharmaceutical or cosmeticcomposition and foam comprising an effective amount of a pharmaceuticalor cosmetic active agent, a hydrophobic solvent, a foamer complex and aliquefied or compressed gas propellant.

The percent by weight Is based on weight foamable composition; where theratio of composition other than propellant to propellant is from about100:1 to about 100:30; or from about 100:3 to about 100:30; or fromabout 100:4 to about 100:25; or from about 100:7 to about 100:17; orfrom, about 100:10 to about 100:14 or from any one of the lower ratiosto any one of the higher ratios.

In one or more embodiments there is provided a composition comprising apropellant having a vapor pressure between about 10 psi and about 130psi. In one or more embodiments there is provided a compositioncomprising a propellant which is hydrocarbon propellant or ahydrofluorocarbon or another environmentally acceptable propellant.

The composition does not contain a surfactant; and the foaming effect isachieved by the addition of the foamer complex, as specified herein. Thehydrophobic solvent is present in a substantial amount. In one or moreembodiments the hydrophobic solvent is at a concentration between about60% to about 95% by weight, or about 70% to about 90% by weight. Inalternative embodiments the formulation, is formulated, withoutpropellant and delivered as a gel, ointment or rub. In one or moreembodiments the composition comprises a concentration between about 1%to about 80% by weight petrolatum and about 15% to about 94% by weighthydrophobic solvent, wherein the total amount of hydrophobic solvent andpetrolatum is at least about 60% by weight. In one or more alternativeembodiments the formulation comprises 0% to about 80% by weightpetrolatum, and about 15% to about 95% by weight hydrophobic solvent,provided that if present the combined amount of hydrophobic solvent andpetrolatum is at least about 60% by weight.

In one or more alternative embodiments the formulation comprises 0% toabout 91% petrolatum and about 4% to about 95% hydrophobic solvent,provided that if present the combined amount of hydrophobic solvent andpetrolatum is at least about 60% by weight. In one or more alternativeembodiments the formulation comprises 0% to about 95% petrolatum andabout 0% to about 95% hydrophobic solvent, provided that if present thecombined amount of hydrophobic solvent and petrolatum is at least about60% by weight.

In certain embodiments the petrolatum is about 1% to about 20% and thehydrophobic solvent is about 75% to about 94% provided that the combinedamount of hydrophobic solvent and petrolatum is at least about 60% byweight. In certain embodiments the petrolatum is about 21% to about 40%and the hydrophobic solvent is about 55% to about 74% provided that thecombined amount of hydrophobic solvent and petrolatum is at least about60% by weight. In certain embodiments the petrolatum is about 41% toabout 60% and the hydrophobic solvent is about 35% to about 54% providedthat the combined amount of hydrophobic solvent and petrolatum is atleast about 60% by weight. In certain embodiments the petrolatum isabout 61% to about 70% and the hydrophobic solvent is about 25% to about34% provided that the combined amount of hydrophobic solvent andpetrolatum is at least about 60% by weight. In certain embodiments thepetrolatum is about 61% to about 80% and the hydrophobic solvent isabout 15% to about 34% provided that the combined amount of hydrophobicsolvent and petrolatum is at least about 60% by weight.

In certain embodiments the petrolatum is about 81% to about 95% and thehydrophobic solvent is about 0.1% to about 14%, provided that thecombined amount of hydrophobic solvent and petrolatum is at least about60% by weight. According to additional embodiments where a petrolatum ispresent the formulation comprises about 1% to about 80% petrolatum andabout 15% to about 94% hydrophobic solvent, provided that the combinedamount of hydrophobic solvent and petrolatum is at least about 60% byweight. In further embodiments petrolatum may be in excess of about 80%(see for example formulation A8 in Table 9, which produced foam ofexcellent quality. In one or more embodiments, there is provided afoamable formulation comprising petrolatum in excess of about 80%,optionally a liquid oil, a fatty alcohol, and a wax, wherein theformulation generates quality breakable foam. In one or moreembodiments, there is provided a foamable formulation comprisingpetrolatum in excess of about 80%, optionally a liquid oil, a fattyalcohol and/or a fatty acid, and/or a wax, wherein the formulationgenerates quality breakable foam. In one or more other embodiments,there is provided a foamable formulation comprising petrolatum in cxccssof about 80%, a liquid oil, and at least one of a fatty alcohol and/or afatty acid, and/or a wax, wherein the formulation generates qualitybreakable foam.

As will be appreciated from the above illustrative examples as theamount of petrolatum is increased the amount of hydrophobic solvent isreduced. Accordingly, different amounts of petrolatum other than theamounts specified can be contemplated with a parallel increase ordecrease in solvent as appropriate. In one or more embodiments whenmineral oil is combined with different oils, high amounts of petrolatumand shea butter quality foam can be obtained with fatty alcohol(s) asthe foamer complex. In one or more embodiments, there is provided afoamable formulation comprising petrolatum, mineral oil, fattyalcohol(s) and optionally shea butter, wherein the formulation generatesquality breakable foam.

Upon dispensing the foamable carrier composition forms a breakable foamthat is stable, yet breaks easily upon application of shear force. Inone or more embodiments the composition is used for intradermal deliveryof the active agent into the skin with minimal or negligible transdermaldelivery. In one or more alternative embodiments a formulation isprovided to achieve intra mucosal delivery. In certain embodiments thecomposition provides for transdermal delivery. In one or moreembodiments the composition can be used for prevention of a disease ordisorder. The composition or foam is applied to a target surface or areain or on which prevention is sought. The composition or foam is appliedto a target surface or area having a dermato logical or mucosal disorderin need of treatment. In other embodiments the composition or foam isused to treat or ameliorate a dermatological or mucosal disease ordisorder. In still further embodiments it may be used to provide aperiod of remission from the dermatological or mucosal disease ordisorder.

According to an embodiment the one or more active agents is selectedfrom the group consisting of adipic acid, an acaricide, an active herbalextract, an age spot and keratose removing agent, an allergen, an alphahydroxyl acid, an analgesic agent, an androgen, an anesthetic, an antiwrinkle agent, an antiacne agent, an antiaging agent, an antiallergicagent, an antiandrogen agent, an antiapoptotic agent, an antibacterialagent, an antibiotic, an antibiotic agent, an antiburn agent, ananticancer agent, an antidandruff agent, an antidepressant, anantidermatitis agent, an antiedemic agent, an antifungal agent, anantihelminth agent, an antihistamine, an anti-hyperkeratosis agent, ananti-infective agent, an antiinflammatory agent, an antiirritant, anantilipemic agent, an antimicrobial agent, an antimycotic agent, anantioxidant, an antiparasitic agent, an anti-photoaging agent, ananti-photodamaging agent, an antiproliferative agent, an antipruriticagent, an antipsoriatic agent, an antirosacea agent, an antiseborrheicagent, an antiseptic agent, an antiswelling agent, an antiviral agent,an anti-wart, agent, an anti-wrinkle agent, an anti-yeast agent, anastringent, azelaic acid, benzoyl chloride, benzoyl peroxide, abeta-hydroxy acid, calcitriol, calcium hypochlorite, carbon, acardiovascular agent, a chemotherapeutic agent, a corticosteroid, adicarboxylic acid, a dihydrotestosterone inhibitor, a disinfectant,doxycycline, an estrogen, a fungicide, fumaric acid, glycolic acid, ahair growth regulator, a haptene, a herbal extract (comprising an activesubstance), a hormonal agent, a hormone, a hydroxy acid, an immunogenicsubstance, an immunomodulator, an immunoregulating agent, animmunostimulant, an immunosuppressant, an immunosuppressive agent, aninsect repellent, an insecticide, iron oxide, a keratolytic agent,lactic acid, a lactam, lidocaine, a local anesthetic agent, alubricating agent, a masking agent, a metal, a metal oxide, minocycline,a mitocide, mometasone fuorate, a neuropeptide, a non-steroidalanti-inflammatory agent, an organo-beryllium compound, anorgano-metallic compound, an oxidizing agent, and organo-boron compound,a pediculicide, a peptide, a pesticide, a photodynamic therapy agent, aprogesterone, a prostaglandin, a protein, a radical scavenger, arefatting agent, a retinoid, a sadative agent, a scabicide, sebacicacid, a sedative, a sedative agent, a self tanning agent, siliconeoxide, silver, a silver compound, a skin protective agent, a skinwhitening agent, a steroid, a steroid hormone, a steroidalanti-inflammatory agent, talc, titanium dioxide, a tellurium compound, atestosterone inhibitor, a tetracycline antibiotic, urea, a ureaderivative, a vasoactive agent, a vasoconstrictor, a vasodilator, avitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin Bderivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitaminD analog, a vitamin D derivative, a vitamin E, a vitamin E derivative, avitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative,a wart remover, a wound healing agent, zinc oxide, zirconium oxide.

In certain embodiments the active agent is a tetracycline antibiotic. Inone or more embodiments the tetracycline is tetracycline,oxytetracycline, demeclocycline, doxycycline, lymecycline, meclocycline,methacycline, minocycline, rolitetracycline, chlorotetracycline ortigecycline. In certain embodiments the tetracycline is a mixture of twoor more tetracyclines. In one or more embodiments the tetracycline istetracycline, minocycline or doxycyline or a salt thereof. In one ormore embodiments the tetracycline is a hydrophobic tetracyline, selectedfrom minocycline and doxycycline. In one or more embodiments thetetracycline is present in a free base form, a hydrate form, a salt formor a complex form. In one or more embodiments the tetracycline is notsoluble or is partially soluble and all or part thereof is suspended inthe composition. In certain, embodiments the tetracycline isminocycline. In certain embodiments the tetracycline is doxycycline. Inone or more embodiments the properties or uses discovered forminocycline can be applied to any tetracycline antibiotic. In certainembodiments the active agent is selected from a group consisting ofmometasone furoate, calcitriol and calciptriol. In certain embodimentsthe active agent is a vitamin D derivative or analog. In certainembodiments the Vitamin D derivative is calcitriol or calcipotriol orthe corticosteroid is mometasone furoate.

According to a further embodiment the active agent, is chemically stablefor at least two months and where the active agent is compatible withthe other ingredients. According to a further embodiment the activeagent is chemically stable for at least three months and where theactive agent is compatible with the other ingredients. According to afurther embodiment the active agent is chemically stable for at leastsix months; or for at least nine months, or for at least twelve months;or for at least, fifteen months; or for at least, eighteen months; orfor at least, twenty one months: or for at least twenty four months.

As is known to one skilled in the art, in some instances a specificactive agent may have more than one activity, function or effect.

In certain embodiments, the inclusion of two or more therapeutic agentsin the foamable pharmaceutical composition is desirable.

In an embodiment the fatty alcohol is a therapeutically active fattyalcohol. The fatty alcohol can be a straight chain fatty alcohol, asaturated fatty alcohol, an unsaturated fatty alcohol, a hydroxylsubstituted fatty alcohol or a branched fatty alcohol. In one or moreembodiments the fatty alcohol has a carbon chain length of 14 to 22carbons.

In an embodiment, the foamable composition comprises a fatty acid. Thefatty acid can be a straight chain fatty acid, a saturated fatty acid,an unsaturated fatty acid, a hydroxyl fatty acid or a branched fattyacid. In an embodiment the fatty acid is a therapeutically active fattyacid. In one or more embodiments the fatty acid is stearic acid.

In an embodiment, the foamable composition comprises a wax. The wax canbe a liquid wax, a solid wax, an animal wax, a vegetable wax, a mineralwax, a natural wax or a synthetic wax. In an embodiment the fatty acidis a therapeutically active wax.

In an embodiment the wax is selected from a list comprising paraffinwax, beeswax, hydrogenated castor oil or mixtures thereof. In one ormore embodiments there is provided a composition comprising a paraffinwax. In one or more embodiments the paraffin wax can have a meltingpoint from about 37° C. In one or more embodiments the paraffin waxcomprises of alkane chains of between about C₂₀H₄₂ to C₄₀H_(82.) In oneor more embodiments the alkane chains are substantially straight chain.In some embodiments branched or unsaturated molecules can be present.Branched chains are sometimes referred to as isoparaffins. In one ormore embodiments the paraffin wax can be selected from the groupconsisting of paraffin wax 58-62° C., paraffin wax 51-53° C., andparaffin wax 42-44° C. or mixtures thereof. In one or more otherembodiments other melting point ranges can be selected such as 125° F.to 135° F.; 127° F. to 130° F.; 130° F. to 135° F.; 135° F. to 145° F.;140° F. to 145° F.; 150° F. to 155° F.; 150° F. to 165° F.: 160° F. to165° F.; or such as 43-46° C.; 46-53° C.; 48-50° C.; 52-54° C.; 53-55°C.; 54-57° C.; 54-58° C.; 58-60° C.; 59-61° C.; 60-62° C.; 62-66° C.;65-68° C.; or any other similar or relative range(s) or mixturesthereof. In one or more embodiments the wax comprises a polyolefin. Inan embodiment the wax is fully refined. In an embodiment it is suitablefor cosmetic use. In an embodiment it is suitable for pharmaceuticaluse. In an embodiment the paraffin wax is soft. In one or moreembodiments the wax is a mixture of two or more waxes. In certainembodiments the mixture of waxes comprises hydrogenated caster oil andbeeswax. In certain embodiments the ratio of beeswax to hydrogenatedcastor oil is about or at least 1:1. In one or more embodiments theratio is between about 1:1: to about 1:10, or between about 1:1 to about1:6, or between about 1:1 to about 1:5.

In one or more embodiments the ratio of fatty alcohol to wax is betweenabout 4:1 to about 1:4.

In an embodiment, the foamable composition is physically and chemicallystable for at least two and preferably at least three months. In anembodiment, the foamable composition containing a vitamin D derivativeor analog is physically and chemically stable for at least three months.In an embodiment, the foamable composition containing calcitriol isphysically and chemically stable for at least three months. In anembodiment, the foamable composition containing a corticosteroid isphysically and chemically stable for at least three months. In anembodiment, the foamable composition containing mometasone furoate isphysically and chemically stable for at least three months. In anembodiment, the foamable composition containing a tetracycline isphysically and chemically stable for at least three months. In anembodiment, the foamable composition containing minocyline is physicallyand chemically stable for at least six months.

In one or more embodiments the drug carrier is formulated substantiallyfree of short chain alcohols, such as, ethanol, propanol or butanol. Inone or more embodiments the drug carrier is formulated essentially freeof short chain alcohols. In one or more specific embodiments the drugcarrier is formulated essentially free of fatty alcohols. In one or morespecific embodiments the drug carrier is formulated essentially free ofderivatives of fatty alcohols or fatty acids. In one or more otherspecific embodiments the drug carrier is formulated essentially free ofpolyols. In one or more other specific embodiments the drug carrier isformulated substantially free of surfactants and/or short chain alcoholsand/or polyols. In one or more other specific embodiments the drugcarrier is formulated essentially free of surfactants and/or short chainalcohols and/or polyols. In one or more embodiments there is provided acomposition which is essentially waterless. In one or more embodimentsthere is provided a surfactant free composition that is also free ofshort chain alcohols and/or polyol-free. In one or more embodimentsthere is provided a substantially polymer free composition. In otherembodiments it is essentially polymer free. In still further embodimentsthe composition is free of polymeric agent. In one or more embodiments apolymeric agent has a Molecular weight of at least about 1000 Daltons.

In one or more embodiments the composition is essentially free of two ormore of water; polymeric agent; surfactant; short chain alcohol; orpolyol. In one or more embodiments the composition is essentially freeof three or more of water; polymeric agent; surfactant; short chainalcohol; or polyol. In one or more embodiments the composition isessentially free of four or more of water; polymeric agent; surfactant;short chain alcohol; or polyol. In one or more embodiments thecomposition is essentially free of water; polymeric agent; surfactant;short chain alcohol; and polyol.

In one or more other specific embodiments the drug carrier is formulatedsubstantially free of elastomers. In one or more other specificembodiments the drug carrier is formulated essentially free ofelastomers. In one or more other specific embodiments the drug carrieris formulated substantially free of silicones. In one or more otherspecific embodiments the drug carrier is formulated essentially free ofsilicones. In one or more other specific embodiments the drug carrier isformulated with less than about 30% silicone, or less than about 25%silicone, or less than about 20% silicone, or less than about 15%silicone, or less than about 10% silicone, or less than about 7.5%silicone, or less than about 5% silicone or less than about 2% silicone;or less than about 1% silicone; or less than about 0.5% silicone.

According to additional embodiments there is provided a substantiallysurfactant free foamable composition comprising:

-   -   a) about 60% to about 95% by weight of a hydrophobic solvent, or        about 1% to about 80% by weight petrolatum and about 15% to        about 94% by weight hydrophobic solvent, wherein if combined the        total amount of hydrophobic solvent and petrolatum is at least        about 60% by weight;    -   b) an oleaginous foamer complex comprising:        -   (1) about 0.1% to about 20% by weight of a fatty alcohol;            and        -   (2) about 0.1% to about 20% by weight of a fatty acid and/or            a wax and/or shea butter;    -   c) a liquefied or compressed gas propellant;        wherein the percent by weight is based on weight foamable        composition; wherein the ratio of composition other than        propellant to propellant is from about 100:3 to about 100:30;        and wherein upon dispensing the foamable carrier composition        forms a breakable foam that breaks easily upon application of        shear force.

According to additional embodiments there is provided a substantiallysurfactant free composition comprising:

-   -   a) about 60% to about 95% by weight of a hydrophobic solvent or        about 1% to about 80% by weight petrolatum and about 15% to        about 94% by weight hydrophobic solvent wherein if combined the        total amount of hydrophobic solvent and petrolatum is at least        about 60% by weight;    -   b) an oleaginous foamer complex comprising:        -   (1) about 0.1% to about 20% by weight of a fatty alcohol;            and        -   (2) about 0.1% to about 20% by weight of a fatty acid and/or            a wax and/or shea butter; or    -   c) an active agent,    -   wherein the active agent is compatible with and chemically        stable in the composition.

In one or more embodiments the active agent is considered chemicallystable when more than about 90% of the active agent does not break downafter a period of two months in the formulation at room temperature. Inone or more embodiments the period is six months. In one or moreembodiments more than about 88% of the active agent does not break down.In one or more embodiments the active agent is chemically stable in thecomposition at 40° C.

According to additional embodiments there is provided a method ofproducing a foamable composition, including:

-   -   1. providing a foamable therapeutic composition including a        therapeutic agent at a therapeutically effective concentration,        a hydrophobic solvent, for example, at a concentration of about        60% to about 95% by w eight, a foamer complex (including at        least two of a fatty alcohol, a fatty acid and a wax);    -   2. introducing the foamable composition in an aerosol packaging        assembly, comprising of a container, suitable for containing a        pressurized product and a valve, capable of extruding a foam;        and    -   3. introducing to the aerosol packaging assembly a liquefied or        compressed gas propellant at a concentration sufficient to        enable the composition to foam and/or to expel the composition        from the canister.

According to further embodiments there is provided a method ofpreventing, treating ameliorating or eliminating a or alleviating adisease or a disorder by selecting and releasing on to a convenientsurface having or anticipated to have a dermatological or mucosaldisorder or disease in need of treatment a safe and effectivepharmaceutical or cosmetic a substantially surfactant free foamablecomposition comprising an effective amount of a pharmaceutical orcosmetic agent, a hydrophobic solvent, a foamer complex and a liquefiedor compressed gas propellant at a concentration of about 3% to about 30%by weight of the total composition; directing the released foam on to atarget on a patient in need; applying a shear force to and spreading thefoam over the target surface such that after a simple rub the foam is nolonger visible to the naked eye as it is absorbed rapidly on to thetarget surface. In one or more embodiments the active agent is aplacebo.

According to further embodiments there is provided a method of treatingor alleviating or preventing a dermatological or mucosal disorder,comprising: applying a substantially surfactant free foamablecomposition comprising to a surface having a dermatological or mucosaldisorder in need of treatment, said composition comprising:

-   -   a) about 60% to about 95% by weight of a hydrophobic solvent or        about 1% to about 80% by weight petrolatum and about 15% to        about 94% by weight hydrophobic solvent wherein if combined the        total amount of hydrophobic solvent and petrolatum is at least        about 60% by weight;    -   b) an oleaginous foamer complex comprising:        -   (1) about 0.1% to about 20% by weight of a fatty alcohol;            and        -   (2) about 0.1% to about 20% by weight of a fatty acid and/or            a wax and/or shea butter;    -   c) at least one active agent    -   d) liquefied or compressed gas propellant;        wherein the percent by weight is based on weight foamable        composition; wherein the ratio of composition other than        propellant to propellant is from about 100:3 to about 100:30;        and wherein upon dispensing the foamable carrier composition        forms a breakable foam that breaks easily upon application of        shear force.

In one or more embodiments there is provided use of a substantiallysurfactant free foamable composition for preventing or treating oralleviating a dermatological or mucosal disorder wherein the disorder ordisease is selected from the group(s) consisting of a bacterialinfection, a benign tumor, a bullous disease, a burn, a chlamydiainfection, a condition which respond to hormone therapy, a cut, adermatitis, a dermatophyte infection, a dermatose, a disorder of a bodycavity, a disorder of cornification, a disorder of the nose, a disorderof the penile urethra or ear canal, a disorder of the rectum, a disorderof the respiratory system, a disorder of the vagina, a disorder whichresponds to hormone replacement therapy, a disorder which responds totransdermal nicotine administration, a disorders of hair follicles, adisorders of sebaceous glands, a disorders of sweating, a fungalinfection, a gonorrhea infection, a gynecological disorders that respondto hormonal therapy, a malignant tumor, a non-dermatological disorderwhich responds to topical or transdermal delivery of an active agent, aparasitic infection, a pelvic inflammation, a pigmentation disorder, ascaling papular diseases, a sexual dysfunction disorder, a sexuallytransmitted disease, a vaginal disorder, a viral infection, a vulvardisorder, a vulvovaginal infection, a wound, a yeast infection, abscess,acne, acne conglobata, acne fulminans, acne scars, acne vulgaris,actinic keratosis, acute and chronic salpingitis, acute febrileneutrophilic dermatosis, acute lymphangitis, acute pelvic inflammatorydisease, acute soft tissue injury, albinism, allergic contactdermatitis, alopecia, alopecia areata, alopecia totalis, alopeciauniversalis, an allergy, an anal abscess or fistula, an anal and rectaldisease, an anal disorder, an anal fissure, an anal wart, an eardisorder, an hormonal disorder, an inflammatory reaction, anintra-vaginal or rectal sexually-transmitted andnon-sexually-transmitted infectious disease, anal cancer, analexcoriation, anal fissures, anal itch, anal pruritus, anal soreness,anal warts, angiomas, arthritis, athlete's foot, atopic dermatitis, backpain, bacterial skin infections, bacterial vaginosis, baldness, basalcell carcinoma, benign tumors, blisters, bromhidrosis, bullous diseases,bullous pemphigoid, burn, calluses, calluses candidiasis, cancer of thecervix, cancer of the vagina, cancer of the vulva, candidal vaginitis,candidiasis, carbuncles, cellulitis, cervical cancer, cervicitis,chancroid, chemical burns, chicken pox, chloasma, cholesteatoma,cholinergic urticaria, chronic dermatitis, chronic effects of sunlight,cold sores, cold urticaria, comedones, constipation, contact dermatitis,corns, creeping eruption, Crohn's disease, cutaneous abscess, cutaneouslarva migrans, cutaneous myiasis, dark spots, delusional parasitosis,Dercum disease, dermatitis, dermatitis herpetiformis, dermatofibroma,dermatological inflammation, dermatological pain, dermatophytoses,dermographism, diaper rash, drug eruptions and reactions, drug-inducedhyperpigmentation, dyshidrotic eczema, dysmenorrhea, dyspareunia,dysplastic nevi, ecthyma, ectodermal dysplasia, ectopic pregnancy,eczema, endometriosis, endometritis, epidermal necrolysis, epidermoidcyst, erysipelas, erythema multiforme, erythema nodosum, erythrasma,exfoliative dermatitis, fallopian tube cancer and gestationaltrophoblastic disease, fecal incontinence, female orgasmic disorder,folliculitis, fungal nail infections, fungal skin infections, furuncles,gangrene, generalized exfoliative dermatitis, genital cancer, genitalherpes, genital ulcer, genital warts, granuloma annulare, granulomainguinale, gynecological neoplasms including endometrial cancer, headlice, hemorrhoids, hepatitis B, herpes, herpes simplex, hidradenitissuppurativa, hirsutism, HIV/AIDS, hives, human papillomavirus (HPV),hyperhidrosis, hyperpigmentation melasma, hypertrichosis, hypohidrosis,hypopigmentation, ichthyosis, impetigo, inflammatory acne, inflammatoryreactions, ingrown nails, intertrigo, irritant contact dermatitis,ischemic necrosis, itching, jock itch, joint pain, Kaposi's sarcoma,keloid, keratinous cyst, keratoacanthoma, keratosis pilaris, lichenplanus, lichen sclerosus, lichen simplex chronicus, linearimmunoglobulin A disease, lipomas, localized pain in general,lymphadenitis, lymphangitis, lymphogranloma venereum, male patternbaldness, malignant melanoma, malignant tumors, mastocytosis, measles,melanoma, midcycle pain, midcycle pain due to ovulation, miliaria,mittelschmerz, moles, molluscum contagiosum, MRSA, mucopurulentcervicitis (MPC), muscle pain, necrotizing fasciitis, necrotizingmyositis, necrotizing subcutaneous infection, necrotizing subcutaneousinfections, nodular papulopustular acne, nongonococcal urethritis (NGU),non-inflammatory acne, nummular dermatitis, oophoritis, oral herpes,osteoarthritis, osteoarthritis, ovarian cancer, ovarian cysts andmasses, paget's disease of the nipples, panniculitis, papules,parapsoriasis paronychia, parasitic infections, parasitic skininfections, paronychial infection, pediculosis, pelvic congestionsyndrome, pelvic inflammatory disease, pelvic pain, pemphigus, perianalpruritus, perianal thrush, perioral dermatitis, photo-allergy,photo-damage, photo-irritation, photosensitivity, pigmentationdisorders, pimples, pityriasis Lichenoides, pityriasis rosea, pityriasisrubra pilaris, poison ivy, poison oak, polyps of the colon and rectum,postinflammatory hyperpigmentation, postinflammatory hypopigmentation,post-operative or post-surgical skin conditions, premenstrual syndrome,pressure sores, pressure ulcers, pressure urticaria, pruritis, pruritusani, pseudofolliculitis barbae, psoriasis, PUPPP, purpura, pustules,pyogenic granuloma, rash, reactions to sunlight, rectal abscess, rectalfistula, rheumatic pain, ringworm, rosacea, roseola, rubella,salpingitis, scabies, scalded skin syndrome, scaling papular diseases,scarring, scleroderma, sebaceous cyst, seborrheic dermatitis, seborrheickeratoses, seborrheic keratosis, sexual arousal disorder, shingles, skinaging, skin cancer, skin neoplasia, skin neoplasms, skin rash, skintags, skin ulcers, sports injuries, squamous cell carcinoma,staphylococcal scalded skin syndrome, stasis dermatitis, Stevens-Johnsonsyndrome, sun spots, sunburn, thermal burns, tinea corporis, tineacruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis,trauma or injury to the skin, Trichomonas vaginalis, trichomoniasis,vaginal cancer, vaginal dryness, vaginismus, varicella zoster virus,viral skin infections, vitamin D deficiency, vitiligo, vulvar cancer,vulvar disorders, vulvar dystrophy, vulvar intraepithelial neoplasia(VIN), vulvar pain, vulvodynia, warts, water hives, wrinkles, xerosis,yeast skin infections, zoster

According to one or more further embodiments the foamable composition,for treatment of a disorder, is able to reduce skin photodamage orradiation damage and photoaging, and more generally to reduce oxidativestress and inflammation in skin pathologies which are known to beaccompanied by apoptotic cell death. In one or more embodiments, thereis provided a composition for use in preventing or ameliorating ortreating photodamage or radiation damage or photoaging or reducingoxidative stress or inflammation in skin pathologies which are known tobe accompanied by apoptic cell death or any two or more thereof.

According to one or more further embodiments the foamable compositioncomprising minocycline, for treatment of a disorder, has properties oractivities selected from a list including regenerative, anti-apoptotic,anti-inflammatory, anti-photodamaging, anti-radiation damage andanti-photoaging. In one or more embodiments, there is provided acomposition for use in preventing or ameliorating or treating adisorder, the minocycline composition having at least one property oractivity selected from, a list including regenerative, anti-apoptotic,anti-inflammatory, anti-photodamaging anti-radiation damage andanti-photoaging.

According to one or more further embodiments the foamable compositioncomprising minocycline for treatment of a disorder, has protectiveand/or therapeutic properties or activities in the case of UVB-inducedskin damage. In one or more embodiments, there is provided a compositioncomprising minocycline for use in preventing protecting from orameliorating or treating UVB-induced skin damage.

According to one or more further embodiments the foamable compositionfor treatment of a disorder that results in apoptosis comprisingminocycline which decreases apoptosis and/or increases cell viability.In one or more embodiments, there is provided a composition comprisingminocycline for use in preventing, protecting from or ameliorating ortreating a disorder with symptoms including increased apoptosis and/ordecreased cell viability, where the formulation acts to decreaseapoptosis and/or increase cell viability. In one or more embodimentsthere is provided a composition for use in decreasing apoptosis and/orincreasing cell viability.

According to one or more further embodiments the disorder treated by thefoamable composition comprising minocycline for use in reducingoxidative stress and inflammation in skin pathologies which are known tobe accompanied by apoptotic cell death including rosacea and impetigo.In one or more embodiments, there is provided a composition for use inpreventing or ameliorating or treating disorders by reducing oxidativestress and inflammation in skin pathologies which are known to beaccompanied by apoptotic cell death including rosacea and impetigo.

According to one of more further embodiments the foamable compositioncomprising minocycline is non-irritant and suitable for ophthalmic useand/or other sensitive targets such as for use internal and/or externalwounds or burns or in skin, body cavities and mucosal membrane. In oneor more embodiments, there is provided a composition, comprisingminocycline, which is non-irritant, for use in preventing orameliorating or treating a disorder and is suitable for ophthalmic useand can be applied on other sensitive targets such as for use oninternal and/or external wounds or burns or in skin, body cavities andmucosal membranes.

Thus in one or more embodiments there is provided a tetracyclinecomposition having regenerative, or anti-apoptotic, oranti-inflammatory, or anti-photodamaging, or anti-photoaging activity,or protective and/or therapeutic properties in the case of UVB-inducedskin damage, or which decreases apoptosis and/or increases cellviability, or in reducing oxidative stress and inflammation in skinpathologies accompanied by apoptotic cell death including rosacea andimpetigo, or antibacterial activity, or any two or more thereof.

According to one or more farther embodiments the foamable compositioncomprising minocycline has antibacterial activity. In certainembodiments the activity is against enterobacteria and mycobacteria. Incertain embodiments the minocycline has antibacterial activity for useagainst enterobacteria and mycobacteria.

According to certain further embodiments the foamable compositioncomprising minocycline has antibacterial activity against at least oneof the species selected from the group consisting of Staphylococcusaureus, Streptococci, Neisseria meningitidis, Streptococcus pyogenes,Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus aureus(MRSA,) Propionbacterium acnes, Acinetobacter, Bacteroides, Haemophilus,Nocardia, M. leprae. In certain embodiments the minocycline hasantibacterial activity for use against at least one of the speciesselected from the group consisting of Staphylococcus aureus,Streptococci, Neisseria, meningitidis, Streptococcus pyogenes,Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus aureus(MRSA,) Propionbacterium acnes, Acinetobacter, Bacteroides, Haemophilus,Nocardia, M. leprae.

In one or more embodiments there is provided a composition comprising ahydrophobic solvent which is a liquid oil, selected from the groupconsisting of a diglyceride, a PPG alkyl ether, a therapeutic oil,acetylated lanolin alcohol, alexandria laurel tree oil, alkyl benzoate,alkyl octanoate, almond oil, an essential oil, an unsaturated orpolyunsaturated oil, apricot stone oil, arachidyl behenate, arachidylpropionate, avocado oil, barley oil, basil oil, beeswax, benzyl laurate,benzyl myristate, benzyl palmitate, bis (octyldodecyl stearoyl) dimerdilinoleate, borage seed oil, butyl myristate, butyl stearate, C12-C15alkyl benzoate, C12-C15 alkyl octanoate, calendula oil, camphor oil,canelle nut tree oil, canola oil, capric/caprylic triglycerides,caprylic/capric triglyceride castor oil, caprylyl methicone, cardamomoil, carrot oil, castor oil, cetearyl ethylhexanoate, cetearylisononanoate, cetearyl octanoate, cetyl acetate, cetyl dimethicone,cetyl ethylhexanoate, cetyl lactate, cetyl myristate, cetyl octanoate,cetyl palmitate, cetyl ricinoleate, citronella oil, clary sage oil,clove oil, cocoglycerides, coconut oil, cod-liver oil, corn oil, cottonoil, cottonseed oil, cyclohexasiloxane, cyclomethicone, Cyclomethicone5-NF (cyclopentasiloxane), cyclotetrasiloxane, cypress oil, decyloleate, diethyleneglycol diethylhexanoate, diethyleneglycoldiisononanoate, diethyleneglycol dioctanoate, diethylhexanoate,diethylhexyl adipate, diethylhexyl malate, diethylhexyl succinate,diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate,diisosteary dimer dilinoleate, diisostearyl fumerate, dimethicone,dimethyl polysiloxane, dioctyl malate, dioctyl sebacate, disopropyladipate, dodecyl oleate, Dow Corning 244 Fluid (cyclotetrasiloxane), Dowcorning 246 Fluid (d6+d5) (cyclohexasiloxane & cyclopentasiloxane),epoxy-modified silicone oil, essential oils, ester derivatives oflanolic acid, ester oils, ethylhexyl cocoate, ethylhexyl ethylhexanoate,ethylhexyl hydroxystarate, ethylhexyl isononanoate, ethylhexylpalmitate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexylstearate, evening primrose oil, fatty acid-modified silicone oil,flaxseed oil, fluoro group-modified silicone oil, frankincense oil,gelled mineral oil, ginger oil, glycereth triacetate, glyceroltriheptanoate, glyceryl oleate, glyceryl trioctanoate, glyceryltriundecanoate, grape seed oil, grapefruit oil, groundnut oil, hard fat,hazelnut oil, heavy mineral oil, hempseed oil, herring oil, hexadecylstearate, hexyl laurate, hydrocarbon oils, hydrogenated castor oil,hyssop oil, isoamyl laurate, isocetearyl octanoate, isocetyl isocetylbehenate, isocetyl lanolate, isocetyl palmitate, isocetyl salicylate,isocetyl stearate, isocetyl stearoyl stearate, isodecyl ethylhexanoate,isodecyl isononanoate, isodecyl oleate, isododecane, isohexadecaneisododecane, isohexadecanol, isohexyl decanoate, isononyl isononanoate,isononyl octanoate, isoparaffin, isopropyl isostearate, isopropyllanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl stearate, isosteary citrate, isosteary salicylate, isostearytartarate, isostearyl behenate, isostearyl erucate, isostearylglycolate, isostearyl isononanoate, isostearyl isostearate, isostearyllactate, isostearyl linoleate, isostearyl linolenate, isostearyl malate,isostearyl neopentanoate, isostearyl palmitate, isotridecylisononanoate, jasmine oil, jojoba oil, lauryl lactate, lavender oil,lemon oil, light mineral oil, liquid paraffin, liquid triglycerides,lucerne oil, maize germ oil, maleated soybean oil, mandarin oil, manukaoil, marjoram oil, marrow oil, MCT oil, methylphenylpolysiloxane, milletoil, mineral oil, myristyl lactate, myristyl myristate, myristylneopentanoate, myristyl propionate, myrrh oil, neopentylglycoldicaprate, neopentylglycol dicaprylate/dicaprate, neroli oil, nutmegoil, octyl palmitate, octyl stearate, octyldodecanol, octyldodecylbehenate, octyldodecyl hydroxystearate, octyldodecyl myristate,octyldodecyl stearoyl stearate, oils from animal origin, oils of plantorigin, oleyl erucate, oleyl lactate, oleyl oleate, olive oil, ordimethiconol, palm oil, passionflower oil, peanut oil, PEG/PPG 18/18dimethicone, pentaerythrityl tetrastearate, petitgrain oil, petrolatum,phenyl trimethicone, phenyltrimethicone,poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer, polyalkylsiloxane, polyalkylaryl siloxane, polyalphaolefin, polyaryl siloxane,polyaryl siloxanes, polyether group-modified silicone oilcyclomethicone, polyether siloxane copolymer, polyether siloxanecopolymers, polyisobutylene, polyolefin, poppy oil, PPG alkyl ethers,PPG-10 cetyl ether, PPG-10 oleyl ether, PPG-11 stearyl ether, PPG-12butyl ether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 stearylether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-2butyl ether, PPG-2 methyl ether, PPG-20 butyl ether, PPG-20 oleyl ether,PPG-22 butyl ether, PPG-23 oleyl ether, PPG-24 butyl ether, PPG-26 butylether, PPG-28 cetyl ether, PPG-3 methyl ether, PPG-3 myristyl ether,PPG-30 butyl ether, PPG-30 cetyl ether, PPG-30 isocetyl ether, PPG-30oleyl ether, PPG-33 butyl ether, PPG-37 oleyl ether, PPG-4 butyl ether,PPG-4 lauryl ether, PPG-4 myristyl ether, PPG-40 butyl ether, PPG-5butyl ether, PPG-50 cetyl ether, PPG-50 oleyl ether, PPG-52 butyl ether,PPG-53 butyl ether, PPG-7 lauryl ether, PPG-9 butyl ether, PPG-9-13butyl ether, propyl myristate, propylene glycol dicaprate, propyleneglycol dicaprylate, propylene glycol myristyl ether acetate, propyleneglycol ricinoleate, rapeseed oil, rosehip oil, rye oil, safflower oil,sage oil, salmon oil, sesame oil, shea butter, silicone oils, soya oil,soybean oil, stearyl caprate, stearyl dimethicone, stearyl heptanoate,stearyl propionate, sunflower oil, sweet almond oil, syntheticisoalkane, sysymbrium oil, syzigium aromaticum oil, tangerine oil, teatree oil, therapeutic oils, tocopheryl acetate, tocopheryl linoleate,tridecyl ethylhexanoate, tridecyl isononanoate, triisocetyl citrate,unsaturated or polyunsaturated oils, vanilla oil, verbena oil, walnutoil, wheat germ glycerides, wheat germ oil, white petrolatum andmixtures thereof.

DETAILED DESCRIPTION

Foamable Composition and Foam Properties

In one or more embodiments, the composition is a gel that when packagedinto an aerosol canister, equipped with a valve and pressurized with aliquid or pressurized gas propellant is capable of releasing a foam ofquality that is breakable upon application of shear force but is notthermolabile at about or close to body temperature (about 36° C.).

The ability to achieve quality foam with a substantial concentration ofhydrophobic solvent without a surfactant and/or without a polymer issurprising, because usually, such solvents are not prone to creating afoam. The challenge is not just to achieve a quality foam but also toattain a formulation that will satisfy a plurality of two, three, four,five, six or more of the following property specificationssimultaneously.

Notably, the pressurized composition is flowable and releases a foamfreely, even though it might be expected that such concentrations of afatty alcohol and fatty acid would make the hydrophobic solvent ‘gel’ or‘semi-solid’.

-   -   1. Uniformity: The composition should be formulated so that it        is and can remain uniform without phase separation or        precipitation overtime. This property is of high importance when        the product is intended to be a pharmaceutical product.    -   2. Flowability: The composition, when placed in an aerosol        container and pressurized with a propellant should be flowable        such that it can be expelled through the canister valve. It        should preferably also be shakable inside the container. These        requirements create a formulation challenge, because non-viscous        flowable and shakable compositions are prone to undergo phase        separation or precipitation.    -   3. Quality: Upon release from the can, the composition should        generate a foam of good or excellent quality having low density        and small bubble size.    -   4. Stability/Breakability: The fine balance between stability        and breakability of the foam coming out of the container is very        delicate: on one hand the foam should preferably not be “quick        breaking”, i.e., it should be at least short term stable upon        release from the pressurized container and not break as a result        of exposure to skin temperature; and on the other hand, it        should be “breakable”, i.e., it should spread easily, break down        and absorb into the skin or membrane upon application of mild        shear force.    -   5. Skin Feeling: To ensure patient, compliance the skin feeling        after application should be pleasant, and greasy or waxy        residues should be minimal.    -   6. Non-irritating: The above requirements should be achieved        with the awareness that formulation excipients, especially        surfactants, can be irritating, and should preferably be        eliminated from the composition or reduced as much as possible.    -   7. Delivery: Finally, the composition should also be designed to        ensure efficient delivery of a therapeutic agent into the target        site of treatment.    -   8. Compatibility: The components of the composition should be        compatible and not react with an active agent.

Based on extensive investigations and trial and error experiments, ithas been found that such properties can be achieved for formulations asdescribed below and which are further advantageous because of theability of hydrophobic solvents to dissolve or suspend certain activeagents while providing an environment for the active agent which assistsin preventing their degradation. In one or more embodiments there isprovided a composition which is adapted to prevent, the degradation ofthe active ingredient during storage in the canister and also uponapplication on the target site of treatment.

In one or more embodiments there is provided prior to adding propellanta solid or semi-solid composition or gel. In one or more embodiments thecomposition or gel is a liquid. Examples of a liquid gel include where apropellant is added to the formulation (which prior to adding thepropellant is a gel) or where the gel is loose or such that whensubjected to gravity will pour or become liquid. In one or moreembodiments the composition is thixotropic.

Compositions

All % values are provided on a weight (w/w) basis.

In one or more embodiments where ever a phrase is used to refer to aconcentration of above X % or below X % it can also include X % or ofabove about X % or below about X % it can also include about X %.

In one or more embodiments the term “about” has its usual meaning in thecontext of pharmaceutical and cosmetic formulations to allow forreasonable variations in amounts that can achieve the same effect. Inone or more embodiments about can encompass a range of plus and minus20%. In one or more embodiments abo ut can encompass a range of plus andminus 10%.

In one or more embodiments there is provided a foamable carriercomposition including:

-   -   1. a hydrophobic solvent    -   2. a foamer complex comprising:        -   i. a first member, comprising about 0.1% to about 20% by            weight of a fatty alcohol; and        -   ii. a second member, comprising about 0.1% to about 20% by            weight of            -   1. a fatty acid; and/or            -   2. a wax; or    -   3. a liquefied or compressed gas propellant.

In one or more certain embodiments shea butter may replace the secondmember.

In one or more embodiments oily emollients are added to provide orimprove a pleasant skin feeling, and/or lubricating effect with reducedfriction. In one or more embodiments volatile silicones are added toreduce greasy feeling. In one or more embodiments waxes are added toimprove rheology or stabilize foam structure. Surfactants play a role infoam formation and induce foam stability. In one or more embodiments theformulation is substantially or essentially free of surfactants. In oneor more alternative embodiments a small amount of surfactant may beadded preferably less than 1%. Scientific literature is not alwaysaccurate and may loosely or even inaccurately describe a substance as asurfactant. For example, fatty alcohols or fatty acids (in the absenceof a base) when used in combination with classic surfactants havesometimes been referred to as surfactants, whereas at best they merelyfunction as an aid to classic surfactant and may loosely be termed as aco-surfactant but they are not able to stabilize an emulsion and achievea stable foam emulsion on their own without the presence of a truesurfactant. (For more detail see “co-surfactant” below.) In the contextof the present application such fatty acids and fatty alcohols are notsurface active agents but are foam adjuvants. Similarly propoxylatedlanolin oil derivatives have been loosely referred to as surfactants. Inthe context herein they are emollients not surfactants. In one or moreembodiments the composition is essentially free of propoxylated lanolinoil derivatives. In one or more embodiments the composition isessentially free of ethoxylated lanolin oil derivatives. In furtherembodiments the compositions are free of such derivatives. In one ormore certain embodiments the composition is free of PPG, lanolin oils,such as PPG 40 PEG 60 lanolin oil. In one or more embodiments foamadjuvants (e.g. fatty alcohols and fatty acids) and additives (such asSiO2 which acts as a thickener and can provide thixotropy) are added toImprove rheology or stabilize foam structure or as a protective agent.In one or more embodiments antioxidants can be used to preventdegradation/oxidation, for example, butylated hydroxytoluene, which is afat soluble antioxidant.

In one or more embodiments the foamable composition is substantiallysurfactant free. In one or more other embodiments it is essentially freeof any surfactants.

Upon release from an aerosol container, the foamable composition formsan expanded thermally stable breakable foam suitable for topicaladministration.

The foamable composition is suitable for administration to various bodyareas, including, but not limited to the skin, a body surface, a bodycavity, a mucosal surface, e.g., the mucosa of the nose, mouth and eye,the ear, the respiratory system, the vagina or the rectum (severally andinterchangeably termed herein “target site”).

In one or more embodiments, the composition is waterless. By waterlessis meant that the composition contains no or substantially no, free orunassociated or absorbed water. It will be understood by a person, ofthe art that to the extent the waterless solvents and substancesmiscible with them of the present disclosure are hydrophilic, they cancontain water in an associated or unfree or absorbed form and may absorbwater from the atmosphere.

According to one or more embodiments, the foamable composition furthercomprises one or more cosmetic active agents or a pharmaceutical activeagents (severally and interchangeably termed herein “active agent”).

In one or more embodiments the carrier comprises an activepharmaceutical or cosmetic agent which degrades in the presence ofwater, and in such cases the presence of water in the composition isclearly not desirable. Thus, in certain preferred embodiments, thecomposition is waterless. In other embodiments the active agent maytolerate the presence of a small amount of water and the waterlesscomposition is substantially non-aqueous. The term “substantiallynon-aqueous” is intended to indicate that the waterless composition haswater content preferably below about 2%, such as, below about 1.5%,below about 1%; or below about 0.5%. In one or more alternativeembodiments, where for example, the formulation is for cosmetic purposesor where the active agent is not sensitive to water the formulation maycontain low amounts of water of up to about 25%. In certain embodimentsthe amount of water is about or less than about 20%. In certainembodiments the amount of water is about or less than about 15%. Incertain embodiments the amount of water is about or less than about 10%.In certain embodiments the amount of water is about or less than about5%. Where water is present the formulation may be an emulsion or mayform micelles or a colloid. In one or more embodiments the emulsionformulation, has some resistance to centrifugation. In one or moreembodiments the emulsion formulation is substantially resistant tocentrifugation at about 1000 rpm for a few minutes or for about up to 10minutes.

In one or more embodiments there is provided a foamable therapeuticcomposition including:

-   -   1. an active agent;    -   2. a hydrophobic solvent    -   3. a foamer complex comprising:        -   i. a first member, comprising about 0.1% to about 20% by            weight of a fatty alcohol; and        -   ii. a second member, comprising about 0.1% to about 20% by            weight of            -   1. a fatty acid; and/or            -   2. a wax; or    -   4. a liquefied or compressed gas propellant.

In one or more embodiments, at least a portion of the therapeutic agentis suspended or dissolved evenly throughout the entire composition.

It has been discovered that formulations containing high amount of ahydrophobic solvents (such as mineral oil) are not prone to foaming.Surprisingly, it has been further discovered that the combination of afatty alcohol and fatty acid and/or a wax has foam boosting propertiesand provides breakable foams of good quality in the absence of customarysurfactants. It has been discovered that fatty alcohols or fatty acidswith a saturated carbon chain of between 16 to 22 carbons combined haveoutstanding foam boosting properties. It has been further discoveredthat the combination of a fatty alcohol with a fatty acid and a wax hasimproved foaming properties. It has been discovered that differentfactors can influence foaming properties. Non limiting examples include:a) the ratio of fatty alcohol to fatty acid e.g. foams of excellentquality that did not collapse after 180 seconds at 36° C. were obtainedwith a ratio of fatty alcohol:fatty acid of 1:1 and a totalconcentration of fatty alcohol together with fatty acid ranging fromabout 7% to about 10%; b) the ratio of beeswax to hydrogenated castoroil; e.g. foams of good quality that did not collapse after 180 secondsat 36° C. were obtained with a ratio of beeswax to hydrogenated castoroil of 1:1 or more, c) ratio of fatty alcohol to wax e.g. foams of goodquality that did not collapse after 180 seconds at 36° C. were obtainedwith a ratio of fatty alcohol to wax of 2:3 to 3:2. d) the type andconcentration of propellant e.g. AP-70 and Tetrafluoroethane improvedfoam quality in comparison to A-46.

Furthermore, the oleaginous formulations of the present invention canprovide foams of good quality in the presence of various activeingredients. It was found for example that compositions of the presentinvention comprising one or more of Doxycycline Hyclate, BetamethasoneValerate, Progesterone, Terbinafine, Metronidazole, Mometasone Furoate,Calcitriol, Calcipotriol and Naproxen can give rise to breakable foamsof good to excellent quality which did not collapse for at least 2minutes at 36° C.

In one or more embodiments, the active agent is a vitamin A or aderivative or analog thereof.

In one or more embodiments, the active agent is a vitamin E or aderivative or analog thereof.

In one or more embodiments, the active agent is a vitamin K or aderivative or analog thereof.

In one or more embodiments, the active agent is a vitamin F or aderivative or analog thereof.

In one or more embodiments, the active agent is vitamin D or aderivative or analog thereof.

In one or more embodiments, the active agent is calcipotriol.

In one or more embodiments, the active agent is calcitriol.

In one or more embodiments, the active agent is corticosteroid.

In one or more embodiments, the active agent is mometasone furoate.

In one or more embodiments, the active agent is doxycycline hyclate.

In one or more embodiments, the active agent is betamethasone valerate.

In one or more embodiments, the active agent is progesterone.

In one or more embodiments, the active agent is terbinafine.

In one or more embodiments, the active agent is metronidazole.

In one or more embodiments, the active agent is naproxen.

In one or more embodiments, the active agent is one or more ofdoxycycline hyclate, betamethasone valerate, progesterone, terbinafine,metronidazole, mometasone furcate, calcitriol, calcipotriol andnaproxen.

In one or more embodiments, the composition is essentially free ofpolyols.

In one or more embodiments, composition is capable of providingintradermal delivery of the active agent into the skin with minimal ornegligible transdermal delivery.

In one or more embodiments, the composition has some preservativeefficacy.

In one or more embodiments, the composition is for use in eyeinfections.

In one or more embodiments, the composition is physically and chemicallystable for at least two months and wherein the active agent iscompatible with and chemically stable in the composition.

In one or more embodiments, the composition, is physically andchemically stable for at least three months and wherein the active agentis compatible with and chemically stable in the composition.

In one or more embodiments, the composition is physically and chemicallystable for at least six months and wherein the active agent iscompatible with and chemically stable in the composition.

It was further found that different waxes had a different influence prefoam formulation (PFF) homogeneity. For example beeswax resulted PFFseparation (decrease in homogeneity), whereas hydrogenated castor oilincreased homogeneity. Paraffin wax 51-53 induced PFF separation inplacebo formulation however homogeneity was surprisingly regained uponaddition of minocycline. In one or more embodiments hydrogenated casteroil is used to prevent separation or to restore homogeneity. In one ormore embodiments a tetracycline is used to prevent separation or torestore homogeneity. In one or more embodiments a paraffin is used toprevent separation or to restore homogeneity.

In one or more embodiments, there is provided a substantially surfactantfree composition comprising:

-   -   a) about 60% to about 95% by weight of a hydrophobic solvent;    -   b) an oleaginous foamer complex comprising:        -   (1) about 0.1% to about 20% by weight of a fatty alcohol;            and        -   (2) about 0.1% to about 20% by weight of a fatty acid and/or            a wax; or    -   c) an active agent,    -   wherein the activc agent is compatible with and chcmically        stable in the composition.        Hydrophobic Solvent

In an embodiment, the composition of the present invention comprises atleast one hydrophobic organic solvent. In one or more embodiments thehydrophobic organic solvent should be compatible with the activeingredient. Oils which are incompatible are omitted. For example,minocycline compositions will be free of pomegranate seed oil. A“hydrophobic organic solvent” (also termed “hydrophobic solvent”) asused herein refers to a material having solubility in distilled water atambient temperature of less than about 1 gm per 100 mL, more preferablyless than about 0.5 gm per 100 mL, and most preferably less than about0.1 gm per 100 mL. It is liquid at ambient temperature. Theidentification of a “hydrophobic solvent”, as used herein, is notintended to characterize the solubilization capabilities of the solventfor any specific active agent or any other component of the foamablecomposition. Rather, such term is provided to aid in the identificationof materials suitable for use as a hydrophobic solvent in the foamablecompositions described herein.

In one or more embodiments the hydrophobic solvent is present at aconcentration of about 60% to about 95% or about 65% to about 90%; orabout 70% to about 90% or about 75% to about 85%.

In one or more embodiments, the composition of the present inventioncomprises at least one hydrophobic solvent, selected from the groupconsisting of an oil including a mineral oil, a hydrocarbon oil, anester oil, a liquid triglyceride oil, an oil of plant origin, an oilfrom, animal origin, an unsaturated or polyunsaturated oil, adiglyceride, a PPG alkyl ether and a silicone oil.

As exemplified herein, members of each of the above listed groups ofhydrophobic solvents have been found to be compatible with hydrophobictetracyclines, such as minocycline and doxycycline.

Non-limiting examples of hydrocarbon oils include mineral oil, liquidparaffin, an isoparaffin, a polyalphaolefin, a polyolefin,polyisobutylene, a synthetic isoalkane, isohexadecane and isododecane.

Non-limiting examples of ester oils include alkyl benzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidylbehenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzylpalmitate, bis (octyldodecyl stearoyl) dimer dilinoleate, butylmyristate, butyl stearate, cetearyl ethylhexanoate, cetearylisononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetylmyristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyloleate, diethyleneglycol diethylhexanoate, diethyleneglycol dioctanoate,diethyleneglycol diisononanoate, diethyleneglycol diisononanoate,diethylhexanoate, diethylhexyl adipate, diethylhexyl malate,diethylhexyl succinate, diisopropyl adipate, diisopropyl dimerate,diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearylfumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexylpalmitate, ester derivatives of lanolic acid, ethylhexyl cocoate,ethylhexyl ethylhexanoate, ethylhexyl hydroxystarate, ethylhexylisononanoate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexylstearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetylisocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetylstearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoylstearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecylisononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate,isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyllanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl stearate, isostearyl behenate, isosteary citrate, isostearylerucate, isostearyl glycolate, isostearyl isononanoate, isostearylisostearate, isostearyl lactate, isostearyl linoleate, isostearyllinolenate, isostearyl malate, isostearyl neopentanoate, isostearylpalmitate, isosteary salicylate, isosteary tartarate, isotridecylisononanoate, isotridecyl isononanoate, lauryl lactate, myristyllactate, myristyl myristate, myristyl neopentanoate, myristylpropionate, octyldodecyl myristate, neopentylglycol dicaprate, octyldodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate,octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecylstearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propylmyristate, propylene glycol myristyl ether acetate, propylene glycoldicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate,maleated soybean oil, stearyl caprate, stearyl heptanoate, stearylpropionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate,tridecyl ethylhexanoate, tridecyl isononanoate and triisocetyl citrate.

Non-limiting examples of liquid triglycerides and oils of plant origininclude alexandria laurel tree oil, avocado oil, apricot stone oil,barley oil, borage seed oil, calendula oil, canelle nut tree oil, canolaoil, caprylic/capric triglyceride castor oil, coconut oil, corn oil,cotton oil, cottonseed oil, evening primrose oil, flaxseed oil,groundnut oil, hazelnut oil, glycereth triacetate, glyceroltriheptanoate, glyceryl trioctanoate, glyceryl triundecanoate, hempseedoil, jojoba oil, lucerne oil, maize germ oil, marrow oil, millet oil,neopentylglycol dicaprylate/dicaprate, olive oil, palm oil,passionflower oil, pentaerythrityl tetrastearate, poppy oil, propyleneglycol ricinoleate, rapeseed oil, rye oil, safflower oil, sesame oil,shea butter, soya oil, soybean oil, sweet almond oil, sunflower oil,sysymbrium oil, syzigium aromaticum oil, tea tree oil, walnut oil, wheatgerm glycerides and wheat germ oil.

Non-limiting examples of PPG alkyl ethers include PPG-2 butyl ether,PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butylether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 stearyl ether,PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-20 butylether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether,PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butylether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether,PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methylether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether,PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleylether, PPG-40 butyl ether, PPG-50 oleyl ether and PPG-11 stearyl ether.Preferred PPG alky ethers according to the present invention includePPG-15 stearyl ether, PPG-2 butyl ether and PPG-9-13 butyl ether.

Non-limiting examples of oils from animal origin include herring oil,cod-liver oil and salmon oil.

The hydrophobic solvent may be an emollient, i.e., a hydrophobic liquidhaving a softening or soothing effect especially to the skin. In someembodiments the liquid oil may contain a solid or semi solid hydrophobicmatter at room temperature.

Essential oil, which is usually a concentrated, hydrophobic liquidcontaining volatile aroma compounds from plants usually conveyingcharacteristic fragrances. Non limiting examples include lavender,peppermint, and eucalyptus. A therapeutic oil is a hydrophobic liquidwhich is said to have a therapeutic effect or to have associated with itcertain healing properties. Therapeutic oils contain active biologicallyoccurring molecules and, upon topical application, exert a therapeuticeffect. Non limiting examples include manuka oil, rosehip oil, whichcontains retinoids and is known to reduce acne and post-acne scars, andtea tree oil, which possesses anti-microbial activity includingantibacterial, antifungal and antiviral properties as well as any othertherapeutically beneficial oil known in the art of herbal medication.Many essential oils are considered “therapeutic oils.” Other nonlimiting examples of essential oils are basil, camphor, cardamom,carrot, citronella, clary sage, clove, cypress, frankincense, ginger,grapefruit, hyssop, jasmine, lavender, lemon, mandarin, marjoram, myrrh,neroli, nutmeg, petitgrain, sage, tangerine, vanilla and verbena.

Some embodiments include silicone oils. Non-limiting examples ofsilicone oils include a cyclomethicone, dimethicone, a polyalkylsiloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a polyethersiloxane copolymer, a poly(dimethylsiloxane)-(diphenyl-siloxane)copolymer, a dimethyl polysiloxane, an epoxy-modified silicone oil, afatty acid-modified silicone oil, a fluoro group-modified silicone oil,a methylphenylpolysiloxane, phenyl trimethicone and a polyethergroup-modified silicone oil. In some embodiments, the silicone oil iscyclomethicone, cyclotetrasiloxane, cyclohexasiloxane,phyenyltrimethicone, Dow corning 246 Fluid (d6+d5) (cyclohexasiloxane &cyclopentasiloxane), Dow Corning 244 Fluid (cyclotetrasiloxane),Cyclomethicone 5-NF (cyclopentasiloxane), stearyl dimethicone,phenyltrimethicone, cetyl dimethicone, caprylyl methicone, PEG/PPG 18/18dimethicone, or dimethiconol.

In one or more embodiments, the hydrophobic solvent may be selected fromcapric/caprylic triglycerides, cyclomethicone; isopropyl myristate,isopropyl palmitate, PPG-15 stearyl ether; octyldodecanol;isohexadecanol, diisopropyl adipate; cetearyl octanoate; MCT oil; heavymineral oil; light mineral oil; coconut oil and soybean oil.

Mixtures of two or more hydrophobic solvents in the same foamablecomposition are contemplated. Furthermore, in certain embodiments, theuse of mixtures of two or more hydrophobic solvents is preferred.

Yet, in certain embodiments, the hydrophobic solvent is a mixture of oneor more liquid hydrophobic solvents, as listed above, together with anadditional hydrophobic substance, which is not liquid (such aspetrolatum). In an embodiment the resultant mixture upon includingpropellant is liquid at ambient temperature. In certain embodiments themain hydrophobic substance in the formulation is a petrolatum, which isa semi solid, in combination with at least one liquid hydrophobicsolvent. For example petrolatum may be added to provide a degree ofocclusivity so that the formulation when applied to a skin surface canoperate to increase skin moisture and/or reduced transdermal water loss.In certain other embodiments a liquid hydrophobic solvent is not added.Fluidity of the composition can be achieved by utilizing liquidizingsolvents (e.g. C12 C15 Alkyl benzoate) and/or liquefied propellantsand/or optionally liquid adjuvants. Inclusion of higher amounts ofpropellant was found useful in order to improve flowability of theformulation from the canister or by using propellants having a highervapor pressure.

In one or more embodiments the hydrophobic solvent is a natural oil,extracted from plants, such as the fruit of olives or avocado or fromtheir seeds, such as, grape seed oil or pomegranate seed oil. Nonlimiting examples of suitable oils, which can also have a therapeuticeffect, include almond oil, avocado oil, calendula oil, coconut oil,cocoglycerides, grape seed oil, jojoba oil, peanut oil, pomegranate seedoil, soy bean oil, and wheat germ oil. In one or more embodiments thehydrophobic solvent is a hydrocarbon based oil, such as light mineraloil or heavy mineral oil. Each oil has its own unique characteristics,as will be appreciated by a man of the art. Some are readily absorbedonto the skin, whist others are heavier or greasy and are less easilyabsorbed. It should be kept in mind that greasiness is a subjectivefeeling. With this caveat in mind pomegranate and avocado are thought tobe oils with a greasier feeling. On the other hand jojoba, almond, grapeseed, calendula and peanut oils are not considered greasy. Somewhere inbetween are soybean, wheat germ and coconut oils. Some oils have astrong natural odor, such as pomegranate seed oil whilst others displaya milder odor, such as soybean, wheat germ, avocado, and almond. Othersdisplay a subtle or almost non existent odor, such as, jojoba, coconut,grape seed, calendula and peanut oil. Sometimes odor is a reflection ofthe level of processing the oil has undergone with a lower ordisappearing odor reflecting a higher level of oil refinement. In anembodiment oils are blended to facilitate good absorption with unctuousocclusive properties. In one or more embodiments fragrance can be addedto mask distinctive odors of oils. In one or more embodiments the oil isa mixture of two or more oils.

Foamer Complex Components

The foamer complex comprises: a first member, comprising about 0.1% toabout 20% by weight of a fatty alcohol; and a second member, comprisingabout 0.1% to about 20% by weight of a fatty acid; and/or a wax. Incertain embodiments the amount of the first and second membersrespectively comprises about 0.4% to about 18% by weight. In certainembodiments the amount of the first and second members each respectivelycomprises about 0.6% to about 12% by weight. In certain embodiments theamount of the first and second members each respectively comprises about0.8% to about 10% by weight. In certain embodiments the amount of thefirst and second members each respectively comprises about 2% to about7% by weight. In certain other embodiments, the concentration of eachmember respectively can be within any one of the following ranges (i)between about 0.1% and about 1%, (ii) between about 1% and about 5%,(iii) between about 5% and about 10%, or (iv) between about 10% andabout 20%. In one or more embodiments, each member is at a concentrationat about 5% to about 10% by weight.

Fatty Alcohol

The foamer complex includes a fatty alcohol. The fatty alcohol whichacts as a foam adjuvant is included in the foamable compositions as amain constituent, to evolve the foaming property of the compositionand/or to stabilize the foam. In one or more embodiments, the fattyalcohol is selected from the group consisting of fatty alcohols having15 or more carbons in their carbon chain, such as cetyl alcohol andstearyl alcohol (or mixtures thereof). Other examples of fatty alcoholsare arachidyl alcohol (C20), behenyl alcohol (C22), tetracosanol,hexacosanol, octacosanoi, triacontanol, tetratriacontanol,1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50). In one or more embodiments the fatty alcohol has a carbon,chain length of 14 to 22 carbons. In one or more other embodiments, thefatty alcohol is selected from the group consisting of fatty alcoholshaving 14 or less carbons in their carbon chain, such as lauryl alcoholand myristyl alcohol. In an embodiment the fatty alcohol is a solid atroom temperature. In an embodiment where the formulation is very viscousliquid fatty acids or fatty alcohols may for example be added, forexample isostearic acid.

In one or more preferred embodiments, the fatty alcohol is cetylalcohol, stearyl alcohol, behenyl alcohol and combinations thereof.Fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain, are suitable as fatty alcohols in the context herein. Incertain embodiments the amount of the fatty alcohol required to supportthe foam system can be approximately inversely related to the length ofits carbon chains. In one or more other embodiments, the fatty alcoholis selected from the group consisting of fatty alcohols having 14 orless carbons in their carbon chain, such as myristyl alcohol. Fattyalcohols are also useful in facilitating improved spreadability andabsorption of the composition.

Fatty alcohols are amphiphatic, however unlike customary surfactants,they cannot usually function as stand-alone surfactants, because oftheir very weak emulsifying capacity. They are occasionally used asnon-ionic co-emulsifiers, i.e., and are commonly used as thickeners(Surfactants in personal care products and decorative cosmetics By LindaD. Rhein, Mitchell Schlossmann Anthony O'Lenick, P., Third Edition,2006, p. 247). Fatty alcohols are generally regarded as safe and theyare not considered as irritants.

An important property of the fatty alcohols used in context of thecomposition disclosed herein is related to their therapeutic propertiesper se. Long chain saturated and mono unsaturated fatty alcohols, e.g.,stearyl alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol(docosanol) have been reported to possess antiviral, antiinfective,antiproliferative and anti-inflammatory properties (see, U.S. Pat. No.4,874,794). Longer chain fatty alcohols, e.g., tetracosanol,hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are alsoknown for their metabolism modifying properties and tissue energizingproperties.

Fatty Acid

The foamer complex further includes a fatty acid. The fatty acid whichacts as a foam adjuvant is included in the foamable compositions toevolve the foaming property of the composition and/or to stabilize thefoam, in one or more embodiments the fatty acid can have 16 or morecarbons in its carbon chain, such as hexadecanoic acid (C16)heptadecanoic acid, stearic acid (C18), arachidic acid (C20), behenicacid (C22), tetracosanoic acid (C24), hexacosanoic acid (C26),heptacosanoic acid (C27), octacosanoic acid (C28), triacontanoic acid,dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid andpentatriacontanoic acid, as well as fatty acids with longer carbonchains (up to C50), or mixtures thereof. In one or more otherembodiments, the fatty acid is selected from the group consisting offatty alcohols having 14 or less carbons in their carbon chain, such asdodecanoic acid myristic acid, myristoleic acid, and lauric acid.

Optionally, the carbon atom chain of the fatty acid may have at leastone double bond; alternatively, the fatty acid can be a branched fattyacid. The carbon chain of the fatty acid also can be substituted with ahydroxyl group, such as 12-hydroxy stearic acid. In one or morepreferred embodiments, the fatty acid is stearic acid.

Waxes

The oleaginous foamer complex may include a wax. The wax which acts as afoam adjuvant is included in the foamable compositions to evolve thefoaming property of the composition and/or to stabilize the foam. Waxrefers to beeswax or another substance with similar properties. The termwax refers to a class of substances with properties similar to beeswax,in respect of (i) plastic behavior at normal ambient temperatures, amelting point above approximately 45° C., (ii) a relatively lowviscosity when melted (unlike many plastics); and (iii) hydrophobicnature. Suitable exemplary waxes which can be incorporated into theformulation include animal, vegetable, mineral or silicone based waxeswhich may be natural or synthetic such as, for example: beeswax, Chinesewax, lanolin (wool wax), shellac wax, bayberry wax, candelilla wax,carnauba wax, castor wax, esparto wax, japan wax, ouricury wax, ricebran wax, soy wax, hydrogenated oil such as hydrogenated castor oil,hydrogenated cottonseed oil, or hydrogenated jojoba oil, mink wax, motanwax, ouricury wax, ozokerite, PEG-6 beeswax, rezowax, spent grain wax,stearyl dimethicone, paraffin waxes, such as paraffin 42-44, 51-53,58-62 wax, and the like and mixtures thereof. In certain embodiments theterm wax can extend to hydrogenated oils. In one or more preferredembodiments, the wax is a beeswax or hydrogenated castor oil.

Paraffin wax is unique among other hydrocarbon chains by having a CST ofabout 25 (e.g., 25.5), which is about in the middle of the hydrophobicrange. Thus, paraffin waxes are somewhat amphipatic which may alsocontribute to foam stability. Notably, in comparison to longerhydrocarbons, such as polyethylene and polypropylene, paraffin wax ismuch more hydrophobic, thereby decreasing the surface tension of thehydrophobic solvents in the composition and facilitating foam formationand stabilization (the CST of polypropylene 31.0 and polyethylene 33.0).

Hydrogenated castor oil consists mainly of triglycerides ofhydroxystearic acid and is a solid wax.

Beeswax contains a high proportion of wax esters (35 to 80%), which arelinear monoesters of straight-chain fatty alcohols with even-numberedcarbon chains from C24 to C36 esterified with straight-chain fatty acidssuch as 16:0 and 18:0 fatty acids some with hydroxyl groups in the ω-2and ω-3 positions. The wax esters consist of C40 to C46 molecularspecies. Also present are free acids (about 14%) and carbohydrates(about 12%) as well as approximately 1% free wax alcohols and stearicesters of fatty acids.

In one or more embodiments, the wax is a polyolefin such aspolyethylene, polypropylene, polymethylpentene, polybutene, a polyolefinelastomer, polyisobutylene, ethylene propylene rubber, ethylenepropylene diene Monomer (M-class) rubber, polyethylene terephthalate,polydicyclopentadiene, linear polyolefins, branched polyolefins, cyclicpolyolefins, low density polyolefins, high density polyolefins,polyolefins with a low molecular weight, polyolefins with a highmolecular weight, halogenated polyolefins and the like and mixturethereof.

In one or more embodiments, the wax is polyvinyl chloride,polyvinylidene chloride, polyvinylidene fluoride, polyvinyl fluoride,polytetrafluoro ethylene, polychlorotrifluoro ethylene, polystyrene,polybutadiene, polyisoprene, polychloroprene, polymethylpentene and thelike and mixture thereof.

In an embodiment the wax is selected from the group consisting ofbeeswax, Chinese wax, lanolin wax, shellac wax, bayberry wax, candelillawax, carnauba wax, castor wax, esparto wax, japan wax, ouricury wax,rice bran wax, soy wax, a hydrogenated oil, hydrogenated castor oil,hydrogenated cottonseed oil, or hydrogenated jojoba oil, mink wax,montan wax, ozokerite, PEG-6 beeswax, rezo wax, spent grain wax, stearyldimethicone, a paraffin wax, paraffin 58-62° C. wax, paraffin 51-53° C.wax, paraffin 42-44° C. wax.

In an embodiment the wax is selected from the waxes, as described in“The Complete Technology Book on Wax and Polishes, Publisher: AsiaPacific Business Press Inc., 2006” as incorporated herein by reference.

In one or more embodiments the wax includes vegetable wax, bayberry wax,candelilla wax, carnauba wax, flower wax, sandy wax, fat wax, cottonwax, esparto wax, fir wax, flax wax, Japan wax, ouricury wax, palmwaxes, cuban palm wax, rice-oil wax, sugar cane wax, ucuhuba wax, orcocoa butter.

In one or more embodiments the wax includes synthetic mineral wax,fischer-tropsch wax, duroxon wax, or polymekon wax.

In one or more embodiments the wax includes miscellaneous syntheticwaxes, albacer wax, atlasene wax, BASF waxes, cardis waxes, ceramid,glyco Waxes, flexo wax, or oxazoline waxes.

Combination of a Fatty Alcohol and a Fatty Acid and/or a Wax

In Example 11, which looks at prior art formulations with a fattyalcohol, alone, a foam of good quality is not obtained. When, however, afatty alcohol (or a mixture of fatty alcohols) is combined with a fattyacid (or a mixture of fatty acids) and/or a wax (or a mixture of waxes),they can, surprisingly, act synergistically to produce a good qualitybreakable foam. These successful combinations of a fatty alcohol and afatty acid or a fatty alcohol and a wax are referred to herein as“foamer complexes”.

In one or more embodiments, the foamer complex is a synergisticcombination of a fatty alcohol (or a mixture of fatty alcohols) and afatty acid (or a mixture of fatty acids).

In one or more embodiments, the foamer complex is a synergisticcombination of a fatty alcohol (or a mixture of fatty alcohols) and awax (or a mixture of waxes).

In one or more embodiments, the foamer complex is a synergisticcombination of a fatty alcohol (or a mixture of fatty alcohols), a fattyacid (or a mixture of fatty acids) and a wax (or a mixture of waxes).

In one or more embodiments the range of ratio of fatty alcohol to fattyacid/wax can be about 100:1 to about 1:100; or about 90:1 to about 1:45;or about 80:1 to about 1:40; or about 70:1 to about 1:35; or about 60:1to about 1:30; or about 50:1 to about 1:25; or about 40:1 to about 1:20;or about 30:1 to about 1:15; or about 20:1 to about 1:10; or about 15:1to about 1:5; or about 10:1 to about 1:1; or any ranges in between suchas 1:20 to 20:1, or preferably from 1:10 to 10:1, or 1:4 to 4:1, or 2:3or 3:2.

Combination of a Fatty Alcohol and a Fatty Acid and/or Shea Butter

In one or more embodiments the foamer complex can be a fatty alcohol andshea butter, a fatty acid and shea butter or a combination of a fattyalcohol and a fatty acid and shea butter. Shea butter may, for example,be used instead of paraffin wax or instead of bees wax or instead ofhydrogenated caster oil or to complement one or more of them. As can beappreciated, from Example 22, wax and/or shea butter comprisingcomplexes can be effective with petrolatum based compositions.

In one or more embodiments oily emollients are added to provide orimprove a pleasant skin feeling, and/or lubricating effect with reducedfriction. In one or more embodiments volatile silicones are added toreduce greasy feeling. In one or more embodiments various waxes areadded to improve rheology or stabilize foam structure.

Propellant

The composition requires the addition of a propellant in order togenerate a foam.

Suitable propellants include volatile hydrocarbons such as butane,propane, isobutene or mixtures thereof. In one or more embodiments ahydrocarbon mixture AP-70 is used. In one or more other embodiments alower pressure hydrocarbon mixture AP-46 is used. Both contain butane,propane, isobutene although in different proportions. AP-70 is composedof about 50% w/w of propane, about 20% w/w of isobutane and about 30%w/w of propane. AP-46 is composed of about 16% w/w of propane, about 82%w/w of isobutane and about 2% w/w of propane. Hydro fluorocarbon (MFC)propellants are also suitable as propellants in the context disclosedherein. Exemplary HFC propellants include 1,1,1,2 tetrafluorethane(Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethylether is also useful. In one or more embodiments use of compressed gases(e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is alsopossible.

In one or more embodiments a combination of at least two propellants,selected from HFC, hydrocarbon propellants, dimethyl ether andcompressed gases is contemplated.

Yet, in additional embodiments, the propellant is a self-foamingpropellant, i.e., a volatile liquid having a boiling point of less thanthe temperature of the target treatment site (such as the skin). Anexample of a post-foaming propellant is isopentane (bp=26° C.).

Any concentration of the propellant, which affords an acceptable foam isuseful in accordance with the present invention. In certain embodimentsthe propellant makes up between about 1% and about 30% of the foamablecomposition, or about 3% and 30%; or about 4% and 25%; and in certainpreferred embodiments between about 5% and about 16% of the composition.In preparing the formulations the ingredients other than propellant arecombined to 100% and the propellant is added thereafter so that theratio of formulation to propellant can range from 100:1 to 100:30; 100:3to 100:30; 100:4 to 100:25 or preferably or preferably 100:5 to 100:16.Yet, in additional embodiments, the ratio of composition other thanpropellant to propellant is between about 100:20 and about 100:50.

In one or more embodiments the propellant can also be used to expelformulation using a bag in can system or a can in can system as will beappreciated by someone skilled in the art. In certain embodiments thepart of the propellant system is in the formulation and part separatefrom the formulation. In this way it is possible to reduce the amount ofsurfactant in the formulation but still provide good expulsion from thecanister, where the foamable formulation is expelled quickly but withoutjetting or noise.

In one or more embodiments a foam formulation is expelled from astandard pressurized canister where the propellant is part offormulation. Formulations can be expelled or helped to be expelled byusing propellant which is separate from the formulation using a bag incan or can in can system. Although, these systems can be used withcompressed air the pressure may not be sufficient to expel theformulation through the device and higher pressure propellant such asAP70 should be selected. In one or more embodiments, the formulation ispackaged in bag in can systems or in can in can system. In one or moreembodiments, the formulation is expelled from the canister using thepressure provided by the propellant mixed with the formulation. In oneor more embodiments, the formulation is expelled from the canister usingthe pressure provided, by the propellant stored in a compartmentsurrounding the formulation. According to other embodiments part of thepropellant system is in the formulation and part of the propellantsystem is separate from the formulation, which is used to expel saidformulation using a bag or can in can system. In this way it is possibleto reduce the amount of propellant within the formulation and avoidunwanted gaseous effects, for example in vaginal applications, but stillprovide good expulsion from the canister, where the foamable formulationis expelled sufficiently quickly but without jetting or noise. So by wayof example, between about 1% to 3%; or between about 2% to 4%; betweenabout 3% to 5% propellant (ratio of formulation to propellant of 100:1to 3; 100:2 to 4; 100:3 to 5; respectively) is part of the formulationand a further amount of propellant is separate form the formulation andhelps expel the formulation. In one or more embodiments a similar amountof propellant is in the formulation and a pump or other mechanical meansis used to provide the additional expulsion force.

Modulating Agent

In one or more embodiments the modulating agent is used in a waterlesscomposition which is surfactant free. The term modulating agent is usedto describe an agent which can improve the stability of or stabilize acarrier or a foamable composition and/or an active agent by modulatingthe effect of a substance or residue present in the carrier orcomposition. The substance or residue may, for example, be acidic orbasic or buffer system (or combinations thereof) and potentially alteran artificial pH in a waterless or substantially non-aqueousenvironment, such as, by modulating the ionic or polar characteristicsand any acidity or basesity balance of a waterless or substantiallynon-aqueous carrier, composition, foamable carrier or foamablecomposition or resultant foam or it may be a chelating or sequesteringor complexing agent or it may be one or more metal ions which may act asa potential catalyst in a waterless or substantially non-aqueousenvironment or it may be an ionization agent or it may be an oxidizingagent.

In an embodiment, the modulating or additional component is a pHadjusting agent or a buffering agent and can be any of the knownbuffering systems used in pharmaceutical or cosmetic formulations aswould be appreciated by a man of the art. It can also be an organicacid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid,an alpha or beta hydroxyl acid an organic base or a nitrogen containingcompound.

In one or more further embodiments the modulating agent is used todescribe an agent, which is a chelating or sequestering or complexingagent that is sufficiently soluble or functional in the waterlesssolvent to enable it to “mop up” or “lock” metal ions such as EDTA orother such pharmaceutically or cosmetically acceptable.

Modulating agents may be added to the compositions of the subjectinvention, preferably from about 0.1% to about 10%, more preferably fromabout 1% to about 5%, of the composition. Where the active agent itselfis the modulating agent alone or in combination with another modulatingagent it will be added at an effective dose which may be outside theseranges. For example azaleic acid may be at about 15% of the composition.In an embodiment sufficient modulating agent is added to achieve anartificial pH in which the active agent is preferably stable. Suchartificial pH may be acidic, may be basic or may be neutral

Further detail regarding modulating agents is found in co-pendingPublished U.S. Patent Application 2008/0206159, which is herebyincorporated in its entirety by reference.

The modulating agent to the foamable composition is useful forstabilizing pharmaceutical and cosmetic active agents which are unstablein certain pH conditions. It is known, for example, that active agents,which contain ester bond in their structure tend to undergo hydrolysisof the ester bond at basic pH levels. Therefore, the addition of anagent, which avoids the formation of basic pH condition, can thus,prevent degradation of such active agents. Many steroid compounds areknown to undergo rearrangement at high pH, and again, adding an acidicmodulating agent helps prevent such degradation. Another example of apH-sensitive active agent is vitamin D, which degrades at low pH levels.In such a case, the addition of a basic modulating agent, such astriethanolamine is useful to maintain acceptable stability of thisactive agent.

It is important to maintain skin surface pH in order to preventsusceptibility to bacterial skin infections or skin damage and disease.Thus, adding a modulating agent, which contributes to the stabilizationof skin pH at the desirable level, is advantageous.

In the same fashion, adding an acidic modulating agent to a foamablecomposition, which is intended for vaginal application is advantageous,since better protection against vaginal infection is attained in pHlower than 4.

In one or more embodiments, the modulating agent may also be apreservative or an antioxidant or an ionization agent. Any preservative,antioxidant or ionization agents suitable for pharmaceutical or cosmeticapplication may be used. Non-limiting examples of antioxidants aretocopherol, tocopherol succinate, ascorbic acid (vitamin C) and itssalts, propyl galate, butylated hydroxy toluene and butyl hydroxyanisol. Non-limiting examples of positive ionization agents are benzylconium chloride, and cetyl pyridium chloride. Non-limiting examples ofnegative ionization agents are sodium lauryl sulphate, sodium lauryllactylate and phospholipids. In one or more embodiments the modulatingagent is a flavonoid for example quercitin and/or rutin.

A safe and effective amount of an anti-oxidant/radical scavenger may beadded to the compositions of the subject invention, preferably fromabout 0.1% to about 10%, more preferably from about 1% to about 5%, ofthe composition.

Ophthalmic Excipients

In one or more embodiments the formulation may comprise excipients thatare suitable for ophthalmic use. By virtue of their suitability forophthalmic use they may in certain embodiments be applicable on othersensitive targets such as for use internal and/or external wounds orburns or in body cavities. Excipients selected as pail of a drug carrierthat can be used with the active pharmaceutical ingredients areidentified by compatibility studies with active ingredients to ascertainwhich are compatible for use with the active pharmaceutical ingredients,for example, by examining which do not react with, and/or promote breakdown of the active pharmaceutical ingredients. In one or moreembodiments, the ophthalmic excipient includes one or more knownophthalmic excipients approved by the FDA in the US.

Oleaginous ointments are viscous preparations, which remain viscous whenapplied to the skin or other body surfaces; and they require extensiverubbing. Because of their viscosity, eye ointments cause blurred visionand consequent low tolerability, especially for long term treatment.Because of their high viscosity, drugs are trapped in the vehicle andcannot migrate through to their target site of action, for example, theskin or the eye.

Liquid, non viscous oleaginous medications are also disadvantageous, asthey spill easily and thus, are very inconvenient to use. In eyetreatment, liquid drops are difficult to apply and they require lying onthe back at rest for accurate administration. Furthermore, because oftheir low viscosity, liquid oil vehicles cannot carry suspended drugs,which tend to precipitate and if the viscosity is not high enough,thereby impairing the uniformity of the therapeutic product.

In one or more embodiments the formulations are not highly viscous. Inone or more other embodiments the formulations do not provide lowviscosity. In one or more embodiments the formulations are thixotropicso that on application of shear force their viscosity decreases and theybecome more flowable. In one or more embodiments the formulations arefoams which are breakable on shear force. In one or more embodiments thefoams are based on thixotropic gel formulations. In one or moreembodiments the viscosity of the formulation prior to addition ofpropellant is more than about 1000 cps and less than about 25,000 cps.In one or more embodiments it is more than about 200 cps and less thanabout 24,000 cps.

Ophthalmic Active Agents

In one or more embodiments the formulation, may comprise active agentsthat are suitable for ophthalmic use. By virtue of their suitability forophthalmic use they may in certain embodiments be applicable on othersensitive targets such as for use internal and/or external wounds orburns or in body cavities. Active agents are selected and combined withproper excipients and eye irritation studies including the HET CAM testcan be preformed to ascertain, those which are non irritant.

It was surprisingly found that substantially surfactant free oleaginousformulations containing 1% or 4% minocycline hydrochloride, demonstratedno signs of irritation. Thus in one or more embodiments, thenon-irritant active agent includes a tetracycline. In one or moreembodiments, the non-irritant active agent includes a minocyline.

Additional Components

In an embodiment, a composition disclosed herein includes one or moreadditional components. Such additional components include but are notlimited to anti perspirants, anti-static agents, bulking agents,cleansers, colorants, skin conditioners, deodorants, diluents, dyes,fragrances, hair conditioners, herbal extracts, humectants, keratolyticagents, modulating agents, pearlescent aids, perfuming agents, pHmodifying or stabilizing agents, skin penetration or permeationenhancers, softeners, solubilizers, sunscreens, sun blocking agents,sunless tanning agents, viscosity modifiers, flavanoids and vitamins. Asis known to one skilled in the art, in some instances a specificadditional component may have more than one activity, function oreffect.

In certain embodiments, the additional component is an oil solublepreservative, or an oil soluble antioxidant, or an oil soluble radicalscavenger, or an oil soluble complexing agent, or an oil soluble pigmentor dye.

Definitions

All % values are provided on a weight (w/w) basis.

By the term “about” herein it is meant as indicated above and that afigure or range of figures can also vary plus or minus up to 30%. So inthis embodiment if a figure of “about 1” is provided then the amount canbe up to 1.3 or from 0.70. In other embodiments it can reflect avariation of plus or minus 20%. In still further embodiments it candescribe a variation of plus or minus 10%. In still further embodimentsit can describe a variation of plus or minus 5%. As will be appreciatedby one of the art there is some reasonable flexibility in formulatingcompositions such that where one or more ingredients are variedsuccessful formulations may still be made even if an amount failsslightly outside the range. Therefore, to allow for this possibilityamounts are qualified by about. In one or more other embodiments thefigures may be read without the prefix about.

The term “thixotropic,” as used herein, means that the formulation showsa decrease in viscosity upon application of shear force. The structureof the formulation breaks down leading to a reduction in viscosity. Whenthe formulation is standing without shear force, this decrease inviscosity is recovered over time. In one or more embodiments, the gelformulation subjected to constant shear rate shows a reduction inviscosity with time. In one or more further embodiments, after thematerial is allowed to rest for a period of time, the viscosityincreases again

The term “waterless,” as used herein, means that the compositioncontains no, or substantially no, free or unassociated or absorbedwater. Similarly, “waterless” or “substantially waterless” carrierscontain at most incidental and trace amounts of water.

By the term “single phase” herein it is meant that after addition ofpropellant to the composition or carrier, the liquid components of thefoamable composition or carrier are fully miscible, and the solidcomponents if any, are either dissolved or suspended in the composition.By substantially a single phase is meant that the composition or carrierafter addition of propellant is primarily or essentially a single phaseas explained above, but may also have present a small amount of materialwhich is capable of forming or may form a separate phase amounting toless than about 5% of the composition or carrier after the addition ofpropellant, preferably less than about 3%, and more preferably less thanabout 3%.

The term “unstable active agent” as used herein, means an active agentwhich is oxidized and/or degraded within less than a day, and in somecases, in less than an hour upon exposure to air, light, skin or waterunder ambient conditions.

The term “co-surfactant” as used herein, means a molecule which on itsown is not able to form and stabilize satisfactorily an oil in wateremulsion but when used in combination with a surfactant theco-surfactant has properties, which can allow it to help surfactants tocreate an emulsion and can boost the stabilizing power or effect of thesurfactant and can include, for example, a fatty alcohol, such as cetylalcohol or a fatty acid such as stearic acid. Cetyl alcohol is a waxyhydrophobic substance that can be emulsified with water using asurfactant. Some substances may have more than one function and forexample, fatty alcohols can in some formulations act as a co-solvent. Incertain circumstances a co-surfactant can itself be converted in to asurfactant or soap by, for example, adding a base, such as,triethanolamine to a fatty acid like stearic acid.

The identification of a “polyol”, as used herein, is an organicsubstance that contains at least two hydroxy groups in its molecularstructure.

In one or more embodiments, the polyol is a diol (a compound thatcontains two hydroxy groups in its molecular structure). Examples ofdiols include propylene glycol (e.g., 1,2-propylene glycol and1,3-propylene glycol), butanediol (e.g., 1,2-butanediol, 1,3-butanediol,2,3-butanediol and 1,4-butanediol), butanediol (e.g., 1,3-butanediol and1,4-butenediol), butynediol, pentanediol (e.g., pentane-1,2-diol,pentane-1,3-diol, pentane-1,4-diol, pentane-1,5-diol, pentane-2,3-dioland pentane-2,4-diol), hexanediol (e.g., hexane-1,6-diol hexane-2,3-dioland hexane-2,56-diol), octanediol (e.g., 1,8-octanediol), neopentylglycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol,tetraethylene glycol, dipropylene glycol and dibutylene glycol.

In one or more embodiments, the polyol is a triol (a compound thatcontains three hydroxy groups in its molecular structure), such asglycerin, butane-1,2,3-triol, butane-1,2,4-triol and hexane-1,2,6-triol.

In one or more embodiments, the polyol is a saccharide. Exemplarysaccharides include, but are not limited to monosaccharide,disaccharides, oligosaccharides and sugar alcohols.

A monosaccharide is a simple sugar that cannot be hydrolysed to smallerunits. Empirical formula is (CH₂O)n and range in size from trioses (n=3)to heptoses (n=7). Exemplary monosaccharide compounds are ribose,glucose, fructose and galactose.

Disaccharides are made up of two monosaccharides joined together, suchas sucrose, maltose and lactose.

In one or more embodiments, the polyol is a sugar alcohol (also known asa polyol, polyhydric alcohol, or polyalcohol) is a hydrogenated form, ofsaccharide, whose carbonyl group (aldehyde or ketone, reducing sugar)has been reduced to a primary or secondary hydroxyl group. They arecommonly used for replacing sucrose in foodstuffs, often in combinationwith high intensity artificial sweeteners to counter the low sweetness.Some exemplary sugar alcohols, which are suitable for use according tothe present invention are mannitol, sorbitol, xylitol, maltitol,lactitol. (Maltitol and lactitol are not completely hydrogenatedcompounds—they are a monosaccharide combined with a polyhydric alcohol.)Mixtures of polyols, including (1) at least one polyol selected from adiol and a triol; and (2) a saccharide are contemplated within the scopeof the present disclosure.

According to some embodiments, the composition is polyol free i.e., freeof polyols. In other embodiments, the composition is substantially freeand comprises less than about 5% final concentration of polyols,preferably less than 2%, more preferably less than 1%. Where aformulation includes insignificant amounts of polyols it is consideredto be essentially free of them.

In an embodiment, the polyol is linked to a hydrophobic moiety. In thecontext of the present disclosure, a polyol linked to a hydrophobicmoiety is still defined as a “polyol” as long as it still contains twoor more free hydroxyl groups.

In an embodiment, the polyol is linked to a hydrophilic moiety. In thecontext of the present disclosure, a polyol linked to a hydrophilicmoiety is still defined “polyol” as long as it still contains two ormore free hydroxyl groups.

The term “water activity” as used herein, activity represents thehydroscopic nature of a substance; or the tendency of a substance thatabsorbs water from its surroundings. Microorganisms require water togrow and reproduce, and such water requirements are best defined interms of water activity of the substrate. The water activity of asolution is expressed as Aw=P/Po, where P is the water vapor pressure ofthe solution and Po is the vapor pressure of pure water at the sametemperature. Every microorganism has a limiting Aw, below which it willnot grow; e.g., for Streptococci, Klebsiella spp, Escherichia coli,Clostridium perfringens, and Pseudomonas spp, the Aw value is 0.95.Staphylococcus aureus is most resistant and can proliferate with an Awas low as 0.86, and fungi can survive at Aw of at least 0.7. In one ormore embodiments, the concentration of the hydrophobic solvent, and/orfoamer complex in the composition is selected to provide an Aw valueselected from the ranges of (1) about 0.8 and about 0.9; (2) about 0.7and about 0.8; and (3) less than about 0.7. By delivering theformulation in a pressurized package does not allow for humidity to beabsorbed by the preparation, and therefore, the water free character ofthe composition cannot be damaged.

In an embodiment no preservative is needed because the formulation is awaterless hydrophobic solvent or oil-based formulation having an Aw(Water Activity) value of less than 0.9, less, or less than about 0.8,or less than about 0.7 or less than about 0.6 and preferably less thanabout 0.5 which is below the level of microbial proliferation.

In one or more embodiments, the hydrophobic carrier composition furthercontains an anti-infective agent, selected from the group of anantibiotic agent, an antibacterial agent, an antifungal agent, an agentthat controls yeast, an antiviral agent and an antiparasitic agent. In apreferred embodiment the anti infective agent comprises a tricyclicantibiotic. Not only can combining the anti-infective effect of ahydrophobic carrier composition, with an anti-infective agent can resultin a synergistic effect, and consequently higher success rate of thetreatment but the combination with the foamer complex achieves aformulation in which the active pharmaceutical ingredient is chemicallystable and the formulation is physically stable as demonstrated hereinin the Examples. Moreover the use of hydrophobic based water freeformulation can maximize the antimicrobial potential of theformulations. Storage in sealed, light and airtight canisters can assistin preserving the formulations.

The identification of a “solvent,” as used herein, is not intended tocharacterize the solubilization capabilities of the solvent for anyspecific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a part in the foamablecarriers described herein.

Substantially Alcohol Free

Lower or short chain alcohols, having up to 5 carbon atoms in theircarbon chain skeleton, such as ethanol, propanol, isopropanol, butanol,iso-butanol, t-butanol and pentanol are considered less desirablesolvents or co-solvents due to their skin-irritating effect. Thus,according to some embodiments, the composition is substantiallyalcohol-free i.e., free of short chain alcohols. In other embodiments,the composition comprises less than about 5% final concentration oflower alcohols, preferably less than 2%, more preferably less than 1%.Where a formulation contains insignificant amounts of short chainalcohols it is considered to be essentially free of them.

Substantially Standard Surfactant Free

Surfactants have been categorized in to various sub classes depending ontheir ionic characteristics, namely non-ionic surfactants, anionic,cationic, zwitterionic, amphoteric and amphiphilic surfactants. The termsurfactant has been often loosely used in the art to include substanceswhich do not function effectively as stand alone surfactants to reducesurface tension between two substances or phases. Reduction of surfacetension can be significant in foam technology in relation to the abilityto create small stable bubbles. For example fatty alcohols, fatty acidsand certain waxes are amphiphatic, are essentially hydrophobic with aminor hydrophilic region and for the purposes of forming an emulsionthey are usually regarded as an oil and thus have a “required” HLBvalue” for the purpose of determining what standard surfactant might beappropriate to use with the oil phase. However unlike standard orcustomary surfactants, these substances are not effective as stand-alonesurfactants in foamable emulsion compositions, because of their veryweak emulsifying capacity and further due to their weak foaming capacityon their own. They are occasionally used in a supporting role asco-emulsifiers, i.e., in combination with a standard surfactant but arecommonly used as thickeners and have successfully been used as foamadjuvants to assist customary surfactants to boost foam quality andstability. For clarification in the context herein whilst the term“standard surfactant” or “customary surfactant” refers herein tocustomary non-ionic, anionic, cationic, zwitterionic, amphoteric andamphiphilic surfactants a fatty alcohol or a fatty acid and certainwaxes are not regarded as a standard surfactant. However, in contrast,an ether or an ester formed from such fatty alcohols or fatty acids canbe regarded as a customary surfactant.

Generally, surfactants are known to possess irritation potential. Oneway that is used to try and reduce potential irritation and drying ofthe skin or mucosa due to surfactants and their repeated use especiallywhen formulations are to be left on the skin, or mucosa rather thanbeing washed off is to use essentially or primarily non ionicsurfactants at preferably low concentrations below 5%. The currentbreakthrough of identifying formulations which produce quality breakablefoam yet omitting customary surfactants from a composition maycontribute to improved tolerability of such a composition and can be animportant advantage. This is especially so when a formulation is to beapplied to a very sensitive target site, and particularly so on arepeated basis.

Non-limiting examples of classes of customary non-ionic surfactantsinclude: (i) polyoxyethylene sorbitan esters (polysorbates), such aspolysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; (ii)sorbitan esters, such as sorbitan monostearate sorbitan monolaurate andsorbitan monooleate; (iii) polyoxyethylene fatty acid esters, such as,PEG-8 stearate, PEG-20 stearate, PEG-40 stearate, PEG-100 stearate,PEG-8 laurate, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-8oleate, PEG-9 oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate andPEG-20 oleate; (iv) PEG-fatty acid diesters, such as PEG-150 distearate;(v) polyethylene glycol (PEG) ethers of fatty alcohols, such as: (vi)glycerol esters, such as glyceryl monostearate, glyceryl monolaurate,glyceryl monopalmitate and glyceryl monooleate; (vii) PEG-fatty acidmono- and di-ester mixtures; (viii) polyethylene glycol glycerol fattyacid esters; (ix) propylene glycol fatty acid esters; (x) mono- anddiglycerides: (xi) sugar esters (mono-, di- and tri-esters of sucrosewith fatty acids) and (xii) polyethylene glycol alkyl phenols.

In certain embodiments, the composition is free of customarysurfactants, or “surfactant-free” and in certain embodiments thefoamable composition is substantially free of customary surfactants, or“substantially surfactant-free”.

In the context herein, the term “substantially surfactant-freecomposition” relates to a composition that contains a total of less thanabout 0.4% of a surfactant selected from the group consisting ofcustomary non-ionic, anionic, cationic, zwitterionic, amphoteric andampholytic surfactants. Preferably, the composition comprises less thanabout 0.2% by weight of a standard surfactant and more preferably lessthan about 0.1%. Non-surfactant or surfactant-free compositions willcomprise no or negligible levels of surface active agents.

In additional embodiments, the term “substantially surfactant-free”relates to a composition wherein the ratio between the foamer complexand the surfactant is between 10:1 or 5:1; or between 20:1 and 10:1 orbetween 100:1 and 20:1.

In certain embodiments, the composition is free or substantially free ofan ionic surfactant. In certain embodiments, the composition is free orsubstantially free of a non-ionic surfactant.

Substantially Polymer-Free

By the term polymeric agent it is intended to mean a compound havingmultiple repeated units such as cellulose polymers, acrylic polymers,block polymers and copolymers. In one or more certain embodiments thepolymeric agent has a molecular weight of in excess of a 1000 Daltons.In one or more embodiments the formulations are substantially polymerfree. In one or more embodiments the formulations are substantiallypolymer free of a polymeric agent selected from the group consisting ofa bioadhesive agent, a gelling agent, a film forming agent and a phasechange agent, being locust bean gum, sodium alginate, sodium casemate,egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthangum, quince seed extract, tragacanth gum, guar gum, cationic guars,hydroxypropyl guar gum, starch, amine-bearing polymers such as chitosan;acidic polymers obtainable from natural sources, such as alginic acidand hyaluronic acid; chemically modified starches and the like,carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetatepolymers, polyvinyl chloride polymers, polyvinylidene chloride polymers,semi-synthetic polymeric materials such as cellulose ethers, such asmethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl cellulose, hydroxy propylmethyl cellulose,methylhydroxyethylcellulose, methylhydroxypropylcellulose,hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose,carboxymethylcellulose carboxymethylhydroxyethylcellulose, and cationiccelluloses, carbomer (homopolymer of acrylic acid is crosslinked with anallyl ether pentaerythritol, an allyl ether of sucrose, or an allylether of propylene); poloxamers (synthetic block copolymer of ethyleneoxide and propylene); polyethylene glycol having molecular weight of1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000) andwhich could function as a hydro alcoholic foam booster. By substantiallypolymer free it is intended to mean less than about 5%, preferably lessthan about 2%. By essentially polymer free it is intended to mean lessthan about 1%, preferably less than about 0.5%. In further embodimentsthey are essentially polymer free and in still further embodiments theyare free of polymcric agents.

In alternative embodiments the formulations may comprise a polymericagent in such case the polymeric agents are oil soluble polymericagents. Non limiting examples of oil-soluble polymeric agents are: Ethylcellulose, alkylated guar gum, trimethylsiloxysilicate, alkyl-modifiedsilicone, polyamide-modified silicone, homopolymers and copolymers ofalkyl methacrylates, alkyl acrylates, and alkyl styrenes polyisobutene,polybutyl metacrylate, polycyclohexylstyrene.

According to one or more embodiments, the composition comprises lessthan about 0.1% by weight of a polymeric agent and more preferably lessthan about 0.05%. Polymer-free compositions will comprise no ornegligible levels of polymeric agents.

In the art, the term polymeric agent can be used loosely to refer to anypolymer. However, in some embodiments polymers that do not have a gelbuilding role but may act in other ways are not excluded from thecompositions. In one or more embodiments a polyether siloxane copolymerand a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer and the like,which can provide a good feeling to the composition are not excluded.

Physical Characteristics of the Foamable Composition and Foam

A foamable composition manufactured according to one or more embodimentsherein is very easy to use. When applied onto the afflicted body surfaceof mammals, i.e., humans or animals, it is in a foam state, allowingfree application without spillage. Upon further application of amechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

In one or more embodiments the foamable composition is a single phasesolution. In one or more embodiments the foamable composition issubstantially a single phase solution. In certain circumstances, wherethe active agent is insoluble and is presented as a homogenoussuspension, the formulation is turbid or cloudy.

In one or more embodiments the foam composition has an acceptableshelf-life of at least one year, or at least two years at ambienttemperature. A feature of a product for cosmetic or medical use is longterm stability. Propellants, which are a mixture of low molecularweight-hydrocarbons, tend to impair the stability. The foamablecompositions herein are surprisingly stable, even in the absence ofcustomary surfactants. Following accelerated stability studies, theydemonstrate desirable texture: they form fine bubble structures that donot break immediately upon contact with a surface, spread easily on thetreated area and absorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam. Compositions containing a substantial amount ofsemi-solid hydrophobic solvents, e.g., white petrolatum, as the mainingredients of the oil phase of the emulsion, will likely exhibit highviscosity and poor flow ability and can be inappropriate candidates fora foamable composition. Thus in one or more embodiments semi-solidhydrophobic solvents are a subsidiary component in the composition, forexample being present at less than about 25%, less than about 20%, lessthan about 15%, less than about 10%, or less than about 5% by weight ofthe foamable composition. In other embodiments they can be present inhigher amounts due to the solvent effect of the propellant diluting theformulation and enabling flowability or where the formulation ispresented as a gel or ointment.

Foam Quality

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof a more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

Foam Density

Another property of the foam is specific gravity or density, as measuredupon release from the aerosol can. Typically, foams have specificgravity of less than 0.50 g/mL or less than 0.12 g/mL, depending ontheir composition and on the propellant concentration. In one or moreembodiments the foam density is about less than 0.3 g/mL.

Shakability

‘Shakability’ means that the composition contains some or sufficientflow to allow the composition to be mixed or remixed on shaking. Thatis, it has fluid or semi fluid properties. Shakability is describedfurther in the section on Tests. In one or more certain limitedembodiments the formulation is poorly shakable but is neverthelessflowable.

Breakability/Collapse Time

A further aspect of the foam is breakability. The balance betweenstability and breakability of the foam coming out of the container isvery delicate: on one hand, the foam should preferably not be “quickbreaking”, i.e., it should be stable upon release from the pressurizedcontainer and not break as a result of exposure to skin temperature; andon the other hand, it should be “breakable”, i.e., it should spreadeasily, break down and absorb into the skin or membrane upon applicationof mild shear force. The breakable foam is thermally stable, yet breaksunder shear force. Shear-force breakability of the foam is clearlyadvantageous over thermally-induced breakability. Thermally sensitivefoams start to collapse immediately upon exposure to skin temperatureand, therefore, cannot be applied on the hand and afterwards deliveredto the afflicted area.

The collapse time of foam represents its tendency to betemperature-sensitive and its ability to be at least stable in the shortterm so as to allow a user sufficient time to comfortably handle andapply the foam to a target, area without being rushed and/or concernedthat, it may rapidly collapse, liquefy and/or disappear. Collapse time,as an indicator of thermal sensitivity, is examined by dispensing agiven quantity of foam and photographing sequentially its appearancewith time during incubation at 36° C. Simple collapse time can bemeasured by applying a foam sample on a body surface like the fingers atnormal body temperature of about 37° C. (Collapse time is furtherdescribed in the Examples).

Oils may cause foam to be thermolabile and “quick breaking” inparticular high concentrations of silicone oils. However, in certainembodiments herein, despite the presence of high oil content, quiteunexpectedly the foam is substantially thermally stable. By“substantially thermally stable” it is meant that the foam uponapplication, onto a warm skin or body surface at about 35-37° C. doesnot collapse within about 30 seconds. Thus, in one or more embodimentsthe simple collapse time of the foam is more than about 30 seconds ormore than about one minute or more than about two minutes, or more thanabout three minutes. In one or more limited embodiments simple collapsetime can be a little shorter than 30 seconds, but not less than about 20seconds. In one or further or alternative embodiments the collapse timeis measured by introducing a sample of foam into an incubator at 36° C.and the collapse time of the foam is more than 30 seconds or more thanabout one minute or more than about two minutes, or more than about twominutes.

Pharmaceutical Composition

The foamable oleaginous composition of the present invention can be usedby itself as a topical treatment of a body surface, as many hydrophobicsolvents such as emollients, unsaturated oils, essential oils ortherapeutic oils that possess cosmetic or medical beneficial effects.Furthermore, it is an ideal vehicle for active pharmaceuticalingredients and active cosmetic ingredients. In the context activepharmaceutical ingredients and active cosmetic ingredients arecollectively termed “active agent” or “active agents”. The absence ofsurfactants in the composition is especially advantageous, since nosurfactant-related adverse reactions are expected from such acomposition. Some surfactants may act to facilitate gelling of thepre-foam formulation. The absence of such surfactants may avoid thisundesirable phenomenon. In one or more embodiments the active agent issoluble in the composition of a phase thereof. In one or more otherembodiments it is partially soluble or insoluble. When partially solubleor insoluble the active agent is presented as a suspension or it can beencapsulated in a carrier.

Suitable active agents include but are not limited to adipic acid, anacaricide, an active herbal extract, an age spot and keratose removingagent, an allergen, an alpha hydroxyl acid, an analgesic agent, anandrogen, an anesthetic, an anti wrinkle agent, an antiacne agent, anantiaging agent, an antiallergic agent, an antiandrogen agent, anantiapoptotic agent, an antibacterial agent, an antibiotic, anantibiotic agent, an antiburn agent, an anticancer agent, anantidandruff agent, an antidepressant, an antidermatitis agent, anantiedemic agent, an antifungal agent, an antihelminth agent, anantihistamine, an anti-hyperkeratosis agent, an anti-infective agent, anantiinflammatory agent, an antiirritant, an antilipemic agent, anantimicrobial agent, an antimycotic agent, an antioxidant, anantiparasitic agent, an anti-photoaging agent, an anti-photodamagingagent, an antiproliferative agent, an antipruritic agent, anantipsoriatic agent, an antirosacea agent, an antiseborrheic agent, anantiseptic agent, an antiswelling agent, an antiviral agent, ananti-wart agent, an anti-wrinkle agent, an anti-yeast agent, anastringent, azelaic acid, benzoyl chloride, benzoyl peroxide, abeta-hydroxy acid, calcitriol, calcium hypochlorite, carbon, acardiovascular agent, a chemotherapeutic agent, a corticosteroid, adicarboxylic acid, a dihydrotestosterone inhibitor, a disinfectant,doxycycline, an estrogen, a fungicide, fumaric acid, glycolic acid, ahair growth regulator, a haptene, a herbal extract (comprising an activesubstance), a hormonal agent, a hormone, a hydroxy acid, an immunogenicsubstance, an immunomodulator, an immunoregulating agent, animmunostimulant, an immunosuppressant, an immunosuppressive agent, aninsect repellent, an insecticide, iron oxide, a keratolytic agent,lactic acid, a lactam, lidocaine, a local anesthetic agent, alubricating agent, a masking agent, a metal, a metal oxide, minocycline,a mitocide, mometasone fuorate, a neuropeptide, a non-steroidalanti-inflammatory agent, an organo-beryllium compound, anorgano-metallic compound, an oxidizing agent, and organo-boron compound,a pediculicide, a peptide, a pesticide, a photodynamic therapy agent, aprogesterone, a prostaglandin, a protein, a radical scavenger, arefatting agent, a retinoid, a sadative agent, a scabicide, sebacicacid, a sedative, a sedative agent, a self tanning agent, siliconeoxide, silver, a silver compound, a skin protective agent, a skinwhitening agent, a steroid, a steroid hormone, a steroidalanti-inflammatory agent, talc, titanium dioxide, a tellurium compound, atestosterone inhibitor, a tetracycline antibiotic, urea, a ureaderivative, a vasoactive agent, a vasoconstrictor, a vasodilator, avitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin Bderivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitaminD analog, a vitamin D derivative, a vitamin E, a vitamin E derivative, avitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative,a wart remover, a wound healing agent, zinc oxide, zirconium oxide.

Encapsulation of an Active Agent

In one or more embodiments, the active agent is encapsulated, inparticles, microparticles, nanoparticles, microcapsules, microspheres,nanocapsules, nanospheres, liposomes, niosomes, polymer matrix,silica-gel, graphite, nanocrystals or microsponges. Such particles canhave various functions, such as (1) protection of the drug fromdegradation; (2) modification of the drug release rate from thecomposition; (3) control of skin penetration, profile; and (4)mitigation of adverse effects, due to the controlled release of theactive agent from the encapsulation particles.

Solubility of an Active Agent

Solubility of the active agent, for example a steroid is an importantfactor in the development of a stable foamable composition according tothe present invention.

For definition purposes, in the context of the present invention, thedescriptive terminology for solubility according to the US Pharmacopoeia(USP 23, 1995, p. 10), the European Pharmacopoeia (EP, 5^(th) Edition(2004), page 7) and several other textbooks used in the art ofpharmaceutical sciences (see for example, Martindale, The ExtraPharmacopoeia, 30^(th) Edition (1993), page xiv of the Preface; andRemington's Pharmaceutical Sciences, 18^(th) Edition (1990), page 208)is adapted:

Parts of Solvent Required Descriptive Term for 1 Part of Solute Verysoluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1,000 Veryslightly soluble From 1,000 to 10,000 Practically insoluble or Insoluble10,000 and over

Thus, in one or more embodiments, the active agent is “soluble”, “freelysoluble” or “very soluble” (as defined above) in the composition. Yet,in certain cases, the active agent is “very slightly soluble”, “slightlysoluble” or “sparingly soluble” in the composition.

Yet, in one or more embodiments, the active agent is insoluble i.e.,“requires 10,000 parts or more of a solvent to be solubilized”, in thecomposition.

In certain embodiments it is desirable that the active agent ismaximally soluble in the composition, because solubility of the activeagents is expected to increase its bioavailability.

Yet, in certain preferred additional embodiments it is desirable thatthe active agent is insoluble or is partially soluble and all or partthereof is suspended in the composition, because, inter alia, itsdegradation is enhanced when it is dissolved. In such cases, thehydrophobic solvent is selected by (1) testing the solubility of saidactive agent in various hydrophobic solvents, followed by (2) inclusionin the composition of such solvents that do not solubilize the activeagent. In one or more embodiments the active agent is presented as asuspension.

It is known that every chemical compound has different solubility indifferent solvents or compositions, and therefore it is not possible toprovide a general list compounds that are not soluble or partiallysoluble or suspended in the composition. However, any active agent, asexemplified in the lists herein, is suitable as insoluble or partiallysoluble or suspended, if visual or microscopic observation demonstratescrystals or particles of such active agent in the oleaginouscomposition.

In one or more further embodiments the active agent is micronized, whichcan assist in delivery into the skin, mucosal membrane and body cavitysurfaces and also aid homogenous distribution within the formulation. Ineffect, part of the active agent is presented to a target in solubleform and part is presented in insoluble form. As the soluble part isabsorbed it may help to form a gradient in which insoluble agentreplaces absorbed agent. In one or more embodiments insoluble agent issuspended. In one or more embodiments the suspension is homogenous. Incertain embodiments the formulation is readily re-suspended andhomogenous on shaking. In certain embodiments the agent is soluble.

In one or more embodiments the active agent is used to prevent a diseaseor disorder. In one or more embodiments the active agent is used totreat or alleviate a disease or disorder. In one or more embodiments theactive agent is used to protect a target. An example of protectionincludes protection from radiation or the effects thereof.

Exemplary Groups of Active Agents

Antibiotics

In the context of the present disclosure, an antibiotic agent is asubstance, that has the capacity to inhibit the growth of or to destroybacteria and other microorganisms.

In one or more embodiments, the antibiotic agent is selected from theclasses consisting beta-lactam antibiotics, aminoglycosides, ansa-typeantibiotics, anthraquinones, antibiotic azoles, antibioticglycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides,antibiotic polyenes, antibiotic polyethers, quinoiones, antibioticsteroides, sulfonamides, tetracycline, dicarboxylic acids, antibioticmetals including antibiotic metal ions, oxidizing agents, a periodate, ahypochlorite, a permanganate, substances that release free radicalsand/or active oxygen, cationic antimicrobial agents, quaternary ammoniumcompounds, biguanides, triguanides, bisbiguanides and analogs andpolymers thereof, naturally occurring antibiotic compounds, includingantibiotic plant oils and antibiotic plant extracts and any one of thefollowing antibiotic compounds including non classified antibioticcompound analogs, derivatives, salts, ions, complexes and mixturesthereof.

Tetracyclines

According to some embodiments, the antibiotic agent is a tetracycline.The tetracyclines (also referred to herein as “tetracyclineantibiotics”) are a group of antibacterials, originally derived fromcertain Streptomyces spp., having the same tetracyclic nucleus,naphthacene, and similar properties. They are usually bacteriostatic butact by interfering with protein synthesis in susceptible organisms.Tetracycline antibiotics are susceptible to degradation by oxidation.

Tetracyclines include, but are not limited to, dihydrosteffimycin,demethyltetracycline, aclacinomycin, akrobomycin, baumycin,bromotetracycline, ectocyclin, chlortetracycline, clomocycline,daunorubicin, demeclocycline, doxorubicin, doxorubicin hydrochloride,doxycycline, lymecyclin, marcellomycin, meclocycline, meclocyclinesulfosalicylate, methacycline, minocycline, minocycline hydrochloride,musettamycin, oxytetracycline, rhodirubin, rolitetracycline, rubomycin,serirubicin, steffimycin, tetracycline and analogs, salts andderivatives thereof.

Chlortetracycline, oxytetracycline, tetracycline, demeclocycline are allnatural products that have been isolated from Streptomyces spp. The morerecent tetracyclines, namely methacycline, doxycycline, and minocycline,are semisynthetic derivatives. Methacycline, like demeclocycline, has alonger half-life than tetracycline. Minocycline is active against sometetracycline-resistant bacteria, including strains of staphylococci.Both doxycycline and minocycline are more lipid-soluble than the othertetracyclines and they penetrate well into tissues. They are thus moresuitable for incorporating into oily or emollient containingformulations. However, they have a place in the treatment of chlamydialinfections, rickettsial infections such as typhus and the spottedfevers, mycoplasmal infections such as atypical pneumonia, pelvicinflammatory disease, Lyme disease, brucellosis, tularaemia, plague,cholera, periodontal disease, and acne. The tetracyclines have also beenuseful in the treatment of penicillin-allergic patients suffering fromvenereal, diseases, actinomycosis, bronchitis, and leptospirosis.Minocycline may sometimes be used in multidrug regimens for leprosy.Doxycycline may be used for the treatment and prophylaxis of malaria; itis also used in the management of anthrax.

In an embodiment the active ingredient may be any one of the followingnon limiting examples chlortetracycline, demeclocycline, doxycycline,lymecycline, meclocycline, methacycline, minocycline, oxytetracycline,rolitetracycline, tetracycline. In a preferred embodiment they aredoxycyline or minocycline.

Tetracycline antibiotics can be incorporated into the formulations ofthe present invention to treat, ameliorate or prevent a multitude ofdisorders responsive to tetracycline antibiotics. The formulations canbe applied topically to the skin or to the genitals or to mucosal,membranes and on and around the eye, sub-gingival and can be appliedinto a wide range of body cavities, including aural, digestive, oral,nasal, urethra, penal, endocervical, rectum, respiratory, and vaginaland tooth pocket. Non limiting examples of applications include eyeinfections, blepharitis, dry eye, inclusion conjunctivitis, glaucoma,inflammatory ocular conditions where bacterial infection or a risk ofbacterial ocular infection exists, neuropathic atrophy (in diabetes),abrasions, injuries, wounds, burns, ulcers, pyoderma, furunculosis,granuloma inguinale, periodontitis, rosacea, post-operation infectionsand tissue reconstruction, trachoma, lymphogranuloma venereum, granulomainguinale, acne, inflammation, sinusitis, neuro-protection, washing out,disinfectation, and stabilization of body cavities, at on around or inthe site of an operation, which for example can provide multipletherapeutic effects, such as, inhibition of post operation adhesions,anti infection, neuro-protection.

Whether delivered as a foam, gel, ointment or suspension the activepharmaceutical tetracycline can be present by weight in the range ofabout 0.2% to about 20%, or at about 0.2%, at about 0.3%, at about 0.4%,at about 0.5%, at about 0.6%, at about 0.7%, at about 0.8%, at about0.9%, at about 1%, at about 1.5%, at about 2%, at about 2.5%, at about3%, at about 3.5% at about 4%, at about 4.5%, at about 5%, at about 6%,at about 7%, at about 8%, at about 9%, at about 10%, at about 12%, or atabout 14%, at about 16%, at about 18%, or at about 20%.

Tetracyclines Eye and Skin Infections

Tetracyclines have been used in ophthalmic ointments for the preventionor treatment of infections of the eye caused by s usceptible bacteria.Although minor skin infections and wounds usually heal withouttreatment, some minor skin wounds do not heal without therapy and it isimpossible to determine at the time of injury which wounds will beself-healing. Therefore, some experts believe that, by reducing thenumber of superficial bacteria, topical anti-infectives are useful forpreventing infection in minor skin injuries (e.g., cuts, scrapes,burns).

Tetracycline hydrochloride may be used topically in the treatment ofinflammatory acne vulgaris. Tetracyclines are usually bacteriostatic inaction, but may be bactericidal in high concentrations or against highlysusceptible organisms.

Tetracyclines appear to inhibit, protein synthesis in susceptibleorganisms primarily by reversibly binding to 30S ribosomal subunits,thereby inhibiting binding of aminoacyl transfer-RNA to those ribosomes.In addition, tetracyclines appear to reversibly bind to 50S ribosomalsubunits. There is preliminary evidence that tetracyclines also altercytoplasmic membranes of susceptible organisms resulting in leakage ofnucleotides and other intracellular components from the cell. At highconcentrations, tetracyclines also inhibit mammalian protein synthesis.

The exact mechanisms by which tetracyclines reduce lesions of acnevulgaris have not been fully elucidated; however, the effect, appears tobe partly the result of the antibacterial activity of the drugs.Following topical application to the skirt of a 0.22% solution oftetracycline hydrochloride in a vehicle containing n-decyl methylsulfoxide (Topicycline®; no longer commercially available in the US),the drug inhibits the growth of susccptiblc organisms (principallyPropionibacterium acnes) on the surface of the skin and reduces theconcentration of free fatty acids in sebum. The reduction in free fattyacids in sebum may be an indirect result of the inhibition oflipase-producing organisms which convert triglycerides into free fattyacids or may be a direct result of interference with lipase productionin these organisms. Free fatty acids are comedogenic and are believed tobe a possible cause of the inflammatory lesions (e.g., papules,pustules, nodules, cysts) of acne. However, other mechanisms also appearto be involved because clinical improvement of acne vulgaris withtopical tetracyclines does not necessarily correspond with a reductionin the bacterial flora of the skin or a decrease in the free fatty acidcontent of sebum. (Martindale Electronic Version 2007).

Tetracyclines, Solubility and Stability

Tetracyclines are known to be unstable in the presence of water, as wellas numerous types of formulation excipients, such as protic solvents,various surfactants and certain oils. We surprisingly discovered thatthe inclusion of tetracyclines in a composition comprising a hydrophobicsolvent and a foamer complex described herein results in a stableproduct, with extended stability of the tetracycline. In an embodiment ahydrophobic solvent is selected by (1) testing the solubility of saidactive agent in various hydrophobic solvents, (2) identifying those thatdo not solubilize the active agent followed by (3) inclusion in thecomposition of such solvents that do not solubilize the active agent. Incertain embodiments the tetracycline is insoluble in the composition.

Doxycyline

According to some embodiments, the tetracycline is doxycycline.Doxycycline is a tetracycline antibiotic and also has anti-inflammatoryand immunomodulatory effects. Doxycycline is a semisynthetictetracycline antibiotic derived from oxytetracycline. In addition toantimicrobial activity, the drug has anti-inflammatory andimmunomodulatory effects. It is available as Doxycycline calcium,doxycycline hyclate and doxycycline monohydrate. Doxycycline hyclate anddoxycycline monohydrate occur as yellow, crystalline powders. Thehyclate is soluble in water and slightly soluble in alcohol; themonohydrate is very slightly soluble in water and sparingly soluble inalcohol. Doxycycline calcium is formed in situ during the manufacturingprocess. Following reconstitution of doxycycline hyclate powder for IVadministration with sterile water for injection, solutions have a pH of1.8-3.3.

The mechanism(s) by which doxycycline reduces inflammatory lesions(papules and pustules) in patients has not been elucidated, but theseeffects may result at least in part from the anti-inflammatory actionsof the drug; other mechanisms may be involved

Doxycycline is used for the treatment of rosacea treatment orprophylaxis of anthrax (including inhalational anthrax [postexposure]),treatment of presumed or confirmed rickettsial infections, includingRocky Mountain spotted fever (RMSF), fever, ehrlichiosis, andanaplasmosis, and for the treatment of Bartonella infections, for thetreatment of brucellosis, for the treatment of Burkholderia Infections,Chlamydial Infections, Lymphogranuloma venereum Psittacosis,Ehrlichiosis and Anaplasmosis, Gonorrhea and Associated Infections,Epididymitis, Proctitis, Granuloma Inguinale (Donovanosis,) LegionellaInfections, Leptospirosis, Lyme Disease, Prophylaxis of Lyme Disease,Erythema Migrans, Early Neurologic Lyme Disease, Lyme Carditis, orBorrelial Lymphocytoma, Lyme Arthritis, Malaria, and prevention,Mycobacterial infections, Mycobacterium marinum Infections, PelvicInflammatory Disease, Parenteral Regimens, Plague, pleural Effusion,Rickettsial Infections, Q Fever, Syphilis, Tularemia, Treatment,Postexposure Prophylaxis.

When reconstituted and diluted with 0.9% sodium chloride or 5% dextrose,doxvcycline hyclate IV solutions containing 0.1-1 mg of doxycycline perml are stable for 48 hours at 25° C.; when reconstituted and dilutedwith Ringer's, 10% invert sugar, Normosol-M® in D5W, Normosol-R® in D5W,Plasma-Lyte® 56 in 5% dextrose, or Plasma-Lyte® 148 in 5% dextrose,doxycycline hyclate IV solutions containing 0.1-1 mg/mL are stable for12 hours at room temperature. The manufacturer states that doxycyclinehyclate solutions prepared with any of these infusion solutions arestable for 72 hours at 2-8° C. when protected from direct sunlight andartificial light; however, after storage in this manner, infusion ofthese solutions must be completed within 12 hours Doxycycline hyclate IVsolutions diluted to a concentration of 0.1-1 mg/mL with lactatedRinger's injection or 5% dextrose in lactated Ringer's injection must beinfused within 6 hours to ensure stability. During infusion, alldoxycycline hyclate IV solutions must be protected from direct sunlight.(Martindale 2007 Electronic Version). Thus it can be seen thatDoxycycline is not stable for more than short periods of a matter ofhours.

Preparations of doxycycline hyclate have an acid pH and incompatibilitymay reasonably be expected with alkaline preparations or with drugsunstable at low pH.

Doxycycline is more active than tetracycline against many bacterialspecies including Streptococcus pyogenes, enterococci, Nocardia spp.,and various anaerobes. Cross-resistance is common although sometetracycline-resistant Staphylococcus aureus respond to doxycycline.Doxycycline is also more active against protozoa, particularlyPlasmodium spp.

Doxycycline is a tetracycline derivative with uses similar to those oftetracycline. It may sometimes be preferred to other tetracyclines inthe treatment of susceptible infections because of its fairly reliableabsorption and its long half-life that permits less frequent (often oncedaily) dosing. It also has the advantage that it can be given (withcare) to patients with renal impairment. However, relatively high dosesmay need to be given for urinary-tract infections because of its lowrenal excretion.

For relapsing fever and louse-borne typhus, for the prophylaxis ofleptospirosis, for periodontiti, for Lymphatic filariasis, forMusculoskeletal and joint disorders and for the treatment of acne.

Minocycline

According to some embodiments, the tetracycline is minocycline.Minocycline hydrochloride is a semisynthetic tetracycline antibioticderived from tetracycline. The drug is usually bacteriostatic in action;it exerts its antimicrobial activity by inhibiting protein synthesis. Itis a yellow crystalline powder that is sparingly soluble in water;slightly soluble in alcohol; practically insoluble in chloroform and inether; soluble in solutions of alkali hydroxides and carbonates. pH of asolution in water containing the equivalent of minocycline 1% is between3.5 and 4.5. Preparations of minocycline hydrochloride have an acid pHand incompatibility may reasonably be expected with alkalinepreparations or with drugs unstable at low pH.

Minocycle is highly sensitive and should be stored in airtightcontainers and protected from light to prevent degradation. Thereforeuse in foamable formulations stored in airtight sealed containers underpressure with propellant may contribute to preserving stability subjectto selection of compatible canisters and accessories.

The instability of Minocycline was confirmed in a compatibility studydescribed herein that demonstrated that different hydrophilic solventswere incompatible with minocyline. Whereas, hydrophobic emollients andwaxes revealed compatibility with Minocyline, except for pomegranateseed oil.

All fatty alcohols, as well some fatty acids (such as stearic acid,oleic acid, palmitic acid) surfactants (sucrose fatty esters however notall of them dissolved in oil) and some additives (aerosil and menthol)were compatible with minocycline. Isostearic acid, ethocel and titaniumdioxide polysorbates, spans, polyoxyethylene alkyl ethers (brij), PEGstearates (myrj) were not compatible.

Addition of water caused rapid degradation of minocycline and additionof antioxidants (alpha-tocopherol, BHA/BHT and propyl gallate) did notprevent such degradation. Thus compatible excipients became incompatiblein the presence of water and addition of antioxidants did not remedythis result.

Surprisingly, it was found that enhanced penetration was achievedwithout the need of adding a hydrophilic solvent and thus degradation ofminocyline could be further reduced or prevented. Minocycline wasdelivered intradermally at sufficient levels to treat skin infectionsbut did not pass through the skin transdermally and therefore topicalapplication should be free from adverse systemic effects.

UVB irradiation of the skin is known to decrease cell viability, totalantioxidant capacity, while increasing the levels of inflammation(pro-inflammatory cytokines secretion) and epidermal cell apoptosis.Photosensitivity, manifested as an exaggerated sunburn reaction on areasof the body exposed to direct sunlight or ultraviolet light, hasoccurred with tetracyclines and Minocycline has been associated withpigmentation of the skin and other tissues.

It has surprisingly discovered that oleaginous formulations containingMinocycline had not only protective properties as known in the art butalso therapeutic properties in the case of UVB-induced skin damage. Cellviability was increased and apoptosis was decreased in a dose-dependantmanner when formulation was applied pre UVB irradiation. Apoptosisactivation was significantly decreased when the formulation was appliedpost UVB irradiation of a skin organ culture. Thus, it may be able toreduce skin photodamage and photoaging, and more generally to reduceoxidative stress and inflammation in skin pathologies which are known tobe accompanied by apoptotic cell death for example rosacea and impetigo.Furthermore the increase in viability of cells indicates thatMinocycline has regenerative properties. Furthermore these propertiesand uses of minocycline may extend to other tetracycline antibiotics.

According to one or more embodiments the substantially surfactant-freeoleaginous formulations comprising a tetracycline, such as, Minocyclinehave protective and therapeutic properties in the case of UVB-inducedskin damage. According to one or more embodiments the substantiallysurfactant-free oleaginous formulations comprising a tetracycline, suchas, Minocycline have properties selected from a list includinganti-apoptotic, anti-inflammatory, anti-photodamaging andanti-photoaging. According to one or more embodiments the substantiallysurfactant-free oleaginous formulations comprising a tetracycline, suchas, Minocycline have activity that decreases apoptosis and increasescell viability. According to one or more embodiments there are providedsubstantially surfactant-free oleaginous formulations comprising atetracycline, such as, Minocycline for use to reduce oxidative stressand inflammation in skin pathologies which are known to be accompaniedby apoptotic cell death for example rosacea and impetigo.

Minocycline has a spectrum of activity and mode of action similar tothat of tetracycline but it is more active against many speciesincluding Staphylococcus aureus, streptococci, Neisseria meningitidis,various enterobacteria, Acinetobacter, Bacteroides, Haemophilus,Nocardia, and some mycobacteria, including M. leprae. It was found in anin-vitro study that Minocycline also inhibited the growth ofStreptococcus pyogenes, Pseudomonas aeruginosa, Staphylococcus aureus,as well as a methicillin-resistant strain of Staphylococcus aureus(MRSA) and Propionbacterium acnes.

Partial cross-resistance exists between minocycline and othertetracyclines but some strains resistant to other drugs of the groupremain sensitive to minocycline, perhaps because of better cell-wallpenetration. Minocycline is a tetracycline derivative with uses similarto those of tetracycline. It is also a component of multidrug regimensfor the treatment of leprosy and has been used in the prophylaxis ofmeningococcal infection to eliminate the carrier state, but the highincidence of vestibular disturbances means that it is not the drug ofchoice for the latter. It has neuroprotective properties. It is beinginvestigated for motor neurone disease, for the management ofHuntington's chorea. It is used in the treatment of rheumatoid arthritisand in the treatment of various skin disorders, including acne.

Steroids

In an embodiment, the active agent is a steroid. In certain embodimentsthe steroid is a corticosteroid, including but not limited to,hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethsone dipropionate, clobetasolvalemate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methyl prednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, aswell as analogs, derivatives, salts, ions and complexes thereof.

In certain embodiments, the steroid is a hormone or a vitamin, asexemplified by pregnane, cholestane, ergostane, aldosterone,androsterone, calcidiol, calciol, calcitriol, calcipotriol,clomegestone, cholesterol, corticosterone, cortisol, cortisone,dihydrotestosterone, ergosterol, estradiol, estriol, estrone,ethinylestradiol, fusidic acid, lanosterol, prednisolone, prednisone,progesterone, spironolactone, timobesone and testosterone, as well asanalogs, derivatives, salts, ions and complexes thereof. For substanceslike calcitriol, very low amounts such as about 0.0001% to about 0.005%by weight, of foam formulation or gel or ointment or suspension, orabout 0.0001%, about 0.0002%, about 0.0003%, about 0.0004%, about0.0005%, about 0.0006%, about 0.0007%, about 0.0008%, about 0.0009%,about 0.001%, about 0.0011%, about 0.0012%, about 0.0013%, about0.0014%, about 0.0015%, about 0.0016%, about 0.0017%, about 0.0018%,about 0.0019%, about 0.002%, about 0.003%, about 0.004%, about 0.005% byweight are effective. In some embodiments the active pharmaceuticalagent, is delivered by more than one route, for example, topically andbody cavity.

In an embodiment, the steroid is mometasone furoate. In certainembodiments it can be used topically to treat psoriasis and dermatitis.In certain other embodiments it can be applied in nasal administrationto treat, disorders, such as, allergic rhinitis and asthma.

NSAID

In an embodiment, the active agent is a non-steroidal anti-inflammatoryagent. In the context a nonsteroidal antiinflammatory agent, (alsotermed herein “NSAID”) is a pharmaceutically active compound, other thana corticosteroid, which affects the immune system in a fashion thatresults in a reduction, inhibition, prevention, amelioration orprevention of an inflammatory process and/or the symptoms ofinflammation and/or the production pro-inflammatory cytokines and otherpro-inflammatory mediators, thereby treating or preventing a diseasethat involves inflammation.

In one or more embodiments, the NSAID is an inhibitor of thecyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are knowntoday: the constitutive cyclooxygenase (COX-1); and the induciblecyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or moreembodiments, the NSAID is selected from the group consisting of a COX-1inhibitor, a COX-2 Inhibitor or a non-selective NSAID, whichsimultaneously inhibits both COX-1 and COX-2.

In one or more embodiments, the NSAID is salicylic acid a salicylic acidderivatives. Exemplary salicylic acid derivative include, in a nonlimiting fashion, aspirin, sodium salicylate, choline magnesiumtrislicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, olsalazine, esters of salicylic acid with a carboxylicacid, esters of salicylic acid with a dicarboxylic acid, esters ofsalicylic acid with a fatty acid, esters of salicylic acid with ahydroxyl fatty acid, esters of salicylic acid with an essential fattyacid, esters of salicylic acid with a polycarboxylic acid, and anycompound wherein salicylic acid is linked to an organic moiety through acovalent bond.

In one or more embodiments, the NSAID is para-aminophenol (e.g.,acetaminophen) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an indole or an indole-aceticacid derivative (e.g., indomethacin, sulindac, etodolac) and salts andderivatives thereof.

In one or more embodiments, the NSAID is an aryl acetic acids (e.g.,tolmetin, diclofenac, ketorolac) and salts and derivatives thereof.

In one or more embodiments, the NSAID is an arylpropionic acid and saltsand derivatives thereof. Exemplary arylpropionic acid derivativeinclude, in a non limiting fashion, are ibuprofen, naproxen,flubiprofen, ketoprofen, fenoprofen, oxaprozin.

In one or more embodiments, the NSAID is anthranilic acids or ananthranilic acid derivative, also termed “fenamates” (e.g., mefenamicacid, meclofenamic acid) and salts and derivatives thereof.

In one or more embodiments, the NSAID is selected from the group ofenolic acids, enolic acid salts, enolic acid esters, amides, anhydridesand salts and derivatives thereof. Non-limiting examples of enolic acidderivatives include oxicams (piroxicam, tenoxicam) andpyrazolidinediones (phenylbutazone, oxyphenthratrazone)

Yet, in additional embodiments, the NSAID is an alkanone (e.g.,nabumetone).

Selective COX-2 inhibitors include, in an exemplary marinerdiaryl-substituted furanones (e.g., Rofecoxib); diaryl-substitutedpyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac); andsulfonamides (e.g., Nimesulide) and salts and derivatives thereof.

Local Anesthetic Agents

In an embodiment, the active agent is a local anesthetic agent. Withoutlimiting the scope, the anesthetic agent can be selected from the groupconsisting of benzocaine, lidocaine, bupivacaine, chlorprocaine,dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,procaine, cocaine, ketamine, pramoxine, phenol, any pharmaceuticallyacceptable salts thereof and mixtures of such anesthetic agents. Anymixture of synergistically beneficial anesthetic agents is contemplated.

Keratolytically Active Agents

A keratolytic agent may be included as an active agent of a foamablecomposition. The term “keratolytically active agent” as used hereinincludes a compound that loosens and removes the stratum corneum of theskin, or alters the structure of the keratin layers of skin.Keratolytically active agents are used in the treatment ofdermatological disorders that involve dry skill, hyperkeratinization(such as psoriasis), skin itching (such as xerosis), acne and rosacea.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. As such, they areused in the treatment of dermatological disorders. Dihydroxybenzene andderivatives thereof have been recognized as potent keratolytic agents.Resorcinol (m-dihydroxybenzene) and derivatives thereof are used inanti-acne preparations. In addition to hydroquinone (p-dihydroxybenzene)having anti-pigmentation properties, hydroquinone is also known to bekeratolytic. These compounds also exhibit antiseptic properties. Cresolsalso possess bactericidal and keratolytic properties.

Vitamin A and vitamin A derivatives, also termed herein “retinoids”,such as retinoic acid, isoretinoic acid, retinol and retinal, as well asadapalene, tazarotene, isotretinoin, acitretin and additional retinoidsknown in the art of pharmaceuticals and cosmetics are another class ofkeratolytically active agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as salicylic acid(o-hydroxybenzoic acid) and salicylic acid salts and pharmaceuticallyacceptable derivatives.

Another class of keratolytically active agents includes urea and ureaderivatives.

Immunomodulators

In an embodiment, the active agent is an immunomodulator.Immunomodulators are chemically or biologically-derived agents thatmodify the immune response or the functioning of the immune system.Immunomodulators suitable for use according to the present inventioninclude, among other options, cyclic peptides, such as cyclosporine,tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus,laflurtimus, laquinimod and imiquimod, as well as analogs, derivatives,salts, ions and complexes thereof. Such compounds, delivered in thefoam, are especially advantageous in skin disorders such as psoriasis,eczema and atopic dermatitis, where the large skin areas are to betreated.

Retinoids

In an embodiment, the active agent is a retinoid. Retinoids suitable foruse according to the present invention include, among other options,retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene,13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene,lycopene, 9-cis-beta-carotene, lutein and zeaxanthin, as well as anyadditional retinoids known in the art of pharmaceuticals and cosmetics;and analogs, derivatives, salts, ions and complexes thereof.

Anti-Acne and Anti-Rosacea Active Agents

In an embodiment, the active agent is an anti-acne or an anti-rosaceaagent. The anti-acne agent can be selected from the group consisting ofresorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids,nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid,isoretinoic acid and other retinoid compounds, adapalene, tazarotene,azelaic acid and azelaic acid derivatives, antibiotic agents, such asminocycline erythromycin and clyndamyein, coal tar, zinc salts andcomplexes, and combinations thereof, in a therapeutically effectiveconcentration.

Antipsoriasis Agents

In an embodiment, the active agent is an anti-psoriasis agent. Suchanti-psoriasis agents can be selected, among other options, from thegroup of keratolytically-active agents, salicylic acid, coal tar,anthralin, corticosteroids, retinoids, photodynamic therapy agents, andvitamin D and derivatives and analogs thereof, including vitamin D3derivatives or analogs such as calcitriol, calcipotriol.

Antiinfective Agents

In an embodiment, the active agent is an anti-infective agent. Suchanti-infective agent can be selected from, the group of an antibioticagent, an antibacterial agent, an antifungal agent, an agent thatcontrols yeast, an antiviral agent and an antiparasitic agent. Exemplaryantiinfective agents are exemplified by beta-lactam antibiotic, anaminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole,metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin,clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxinB, an antibiotic polyene, an antibiotic polyether, an antibioticquinolone, an antibiotic steroid, fucidic acid, mupirocin,chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal,silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, anoxidizing agent, iodine, iodate, a periodate, a hypochlorite, apermanganate, a substance that release free radicals and/or activeoxygen, a cationic antimicrobial agent, a quaternary ammonium compound,a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymericbiguanide and a naturally occurring antibiotic compound, as well asanalogs, derivatives, salts, ions and complexes thereof.

The Foamable Composition Essential Ingredients as Active Agents

In certain embodiments, hydrophobic solvent possesses therapeuticproperties on its own and therefore, it can be regarded as “activeagent.” For example, some essential oils kill microorganisms and can beeffective in the treatment or prevention of conditions that involvemicrobial infection, such as bacterial, fungal and viral conditions.Additionally, the occlusive effect of hydrophobic solvents is useful forthe treatment of conditions which involve damaged skin, such aspsoriasis or atopic dermatitis. The combination of a hydrophobic solventand a therapeutically effective fatty alcohol or fatty acid may afford asynergistic beneficial effect in conditions characterized, for example,by infection and/or inflammation.

Combination of Active Agents

Several disorders involve a combination of more than one etiologicalfactor; and therefore, the use of more that, one active agents isadvantageous. For example, psoriasis involves excessive cellproliferation and inadequate cell differentiation as well asinflammation. Atopic dermatitis involves keratinocyte growthabnormality, skin dryness and inflammation. Bacterial, fungal and viralinfections involve pathogen colonization at the affected site andinflammation. Hence, in many cases, the inclusion of a combination ofactive agents in the foamable pharmaceutical composition can bedesirable. Thus, in one or more embodiments, the foamable compositionfurther includes at least two active agents, in a therapeuticallyeffective concentration.

In an embodiment one of the active agents is a vitamin, a vitaminderivative or analogue thereof. In a preferred embodiment the vitamin,vitamin derivative or analogue thereof is oil soluble.

Microsponges

Microsponges (or microspheres) are rigid, porous and spongelike roundmicroscopic particles of cross-linked polymer beads (e.g., polystyreneor copolymers thereof), each defining a substantially noncollapsiblepore network. Microsponges can be loaded with an active ingredient andcan provide a controlled time release of the active Ingredient to skinor to a mucosal membrane upon application of the formulation. The slowrelease Is intended to reduce irritation by the active agent.Microsponge® delivery technology was developed by Advanced PolymerSystems. In one or more embodiments the composition comprises one ormore active agents loaded into Microsponges with a waterless carrierdescribed herein, which may also comprise a modulating agent.

Fields of Applications

The foamable carrier of the present disclosure is suitable for treatingany inflicted surface. In one or more embodiments, foamable carrier issuitable for administration to the skin, a body surface, a body cavityor mucosal surface, e.g., the cavity and/or the mucosa of the nose,mouth, eye, respiratory system, vagina, urethra or rectum and the earcanal (severally and interchangeably termed herein “target site”).

The foamable carrier of the present disclosure is also suitable forpreventing a disorder or disease prior to its onset. The foamablecarrier comprising for example a tetracycline may be applied to a bodysurface or a body cavity to try and prevent apoptosis, a disorder ordisease prior to onset thereof. For example, prior to an anticipatedinflammatory reaction or risk thereof, or prior to an anticipated onsetof apoptosis or a risk thereof, or prior to an anticipated onset ofinflammatory cytokines or risk thereof prior to a medical procedurerequiring intervention such as chemo therapy; radiotherapy, photodynamictherapy, laser therapy, etc. An simple example of prevention use iswhere the foam comprising a tetracycline (or the formulation prior toaddition of propellant) is applied to the skin surface surrounding botheyes.

According to another embodiment a non-limiting list of disorders where atetracycline antibiotic might be used to prevent a disease or disorderis provided, which includes prophylaxis of gonococcal and chlamydialophthalmia, neonatal conjunctivitis, periodontal disease, postoperativetetracycline, prophylaxis in pregnancy termination, for prevention ofskin rash/acneiform skin eruption during cancer therapy, intraoperativetopical tetracycline sclerotherapy following mastectomy for preventionof postoperative mastectomy seromas etc.

By selecting a suitable active agent, or a combination of at least twoactive agents, the foamable composition of the present disclosure isuseful in preventing or treating an animal or a human patient having anyone of a variety of dermatological or mucosal diseases or disorders; inalleviating such diseases or disorders; or where such agent or agentshave shown proficiency in preventative therapy in preventing suchdiseases or disorders, including but not limited to a bacterialinfection, a benign tumor, a bullous disease, a burn, a chlamydiainfection, a condition which respond to hormone therapy, a cut, adermatitis, a dermatophyte infection, a dermatose, a disorder of a bodycavity, a disorder of cornification, a disorder of the nose, a disorderof the penile urethra or ear canal, a disorder of the rectum, a disorderof the respiratory system, a disorder of the vagina, a disorder whichresponds to hormone replacement therapy, a disorder which, responds totransdermal nicotine administration, a disorders of hair follicles, adisorders of sebaceous glands, a disorders of sweating, a fungalinfection, a gonorrhea infection, a gynecological disorders that respondto hormonal therapy, a malignant tumor, a non-dermatological disorderwhich responds to topical or transdermal delivery of an active agent, aparasitic infection, a pelvic inflammation, a pigmentation disorder, ascaling papular diseases, a sexual dysfunction disorder, a sexuallytransmitted disease, a vaginal disorder, a viral infection, a vulvardisorder, a vulvovaginal infection, a wound, a yeast infection, abscess,acne, acne conglobata, acne fulminans, acne scars, acne vulgaris,actinic keratosis, acute and chronic salpingitis, acute febrileneutrophilic dermatosis, acute lymphangitis, acute pelvic inflammatorydisease, acute soft tissue injury, albinism, allergic contactdermatitis, alopecia, alopecia areata, alopecia totalis, alopeciauniversalis, an allergy, an anal abscess or fistula, an anal and rectaldisease, an anal disorder, an anal fissure, an anal wart, an eardisorder, an hormonal disorder, an inflammatory reaction, anintra-vaginal or rectal sexually-transmitted andnon-sexually-transmitted infectious disease, anal cancer, analexcoriation, anal fissures, anal itch, anal pruritus, anal soreness,anal warts, angiomas, arthritis, athlete's foot, atopic dermatitis, backpain, bacterial skin infections, bacterial vaginosis, baldness, basalcell carcinoma, benign tumors, blisters, bromhidrosis, bullous diseases,bullous pemphigoid, burn, calluses, calluses candidiasis, cancer of thecervix, cancer of the vagina, cancer of the vulva, candidal vaginitis,candidiasis, carbuncles, cellulitis, cervical cancer, cervicitis,chancroid, chemical burns, chicken pox, chloasma, cholesteatoma,cholinergic urticaria, chronic dermatitis, chronic effects of sunlight,cold sores, cold urticaria, comedones, constipation, contact dermatitis,corns, creeping eruption, Crohn's disease, cutaneous abscess, cutaneouslarva migrans, cutaneous myiasis, dark spots, delusional parasitosis,Dercum disease, dermatitis, dermatitis herpetiformis, dermatofibroma,dermatological inflammation, dermatological pain, dermatophytoses,dermographism, diaper rash, drug eruptions and reactions, drug-inducedhyperpigmentation, dyshidrotic eczema, dysmenorrhea, dyspareunia,dysplastic nevi, ecthyma, ectodermal dysplasia, ectopic pregnancy,eczema, endometriosis, endometritis, epidermal necrolysis, epidermoidcyst, erysipelas, erythema multiforme, erythema nodosum, erythrasma,exfoliative dermatitis, fallopian tube cancer and gestationaltrophoblastic disease, fecal incontinence, female orgasmic disorder,folliculitis, fungal nail infections, fungal skin infections, furuncles,gangrene, generalized exfoliative dermatitis, genital cancer, genitalherpes, genital ulcer, genital warts, granuloma annulare, granulomainguinale, gynecological neoplasms including endometrial cancer, headlice, hemorrhoids, hepatitis B, herpes, herpes simplex, hidradenitissuppurativa, hirsutism, HIV/AIDS, hives, human papillomavirus (HPV),hyperhidrosis, hyperpigmentation melasma, hypertrichosis, hypohidrosis,hypopigmentation, ichthyosis, impetigo, inflammatory acne, inflammatoryreactions, ingrown nails, intertrigo, irritant contact dermatitis,ischemic necrosis, itching, jock itch, joint pain, Kaposi's sarcoma,keloid, keratinous cyst, keratoacanthoma, keratosis pilaris, lichenplanus, lichen sclerosus, lichen simplex chronicus, linearimmunoglobulin A disease, lipomas, localized pain in general,lymphadenitis, lymphangitis, lymphogranloma venereum, male patternbaldness, malignant melanoma, malignant tumors, mastocytosis, measles,melanoma, midcycle pain, midcycle pain due to ovulation, miliaria,mittelschmerz, moles, molluscum contagiosum, MRSA, mucopurulentcervicitis (MPC), muscle pain, necrotizing fasciitis, necrotizingmyositis, necrotizing subcutaneous infection, necrotizing subcutaneousinfections, nodular papulopustular acne, nongonococcal urethritis (NGU),non-inflammatory acne, nummular dermatitis, oophoritis, oral herpes,osteoarthritis, osteoarthritis, ovarian cancer, ovarian cysts andmasses, paget's disease of the nipples, panniculitis, papules,parapsoriasis paronychia, parasitic infections, parasitic skininfections, paronychial infection, pediculosis, pelvic congestionsyndrome, pelvic inflammatory disease, pelvic pain, pemphigus, perianalpruritus, perianal thrash, perioral dermatitis, photo-allergy,photo-damage, photo-irritation, photosensitivity, pigmentationdisorders, pimples, pityriasis Lichenoides, pityriasis rosea, pityriasisrubra pilaris, poison ivy, poison oak, polyps of the colon and rectum,postinflammatory hyperpigmentation, postinflammatory hypopigmentation,post-operative or post-surgical skin conditions, premenstrual syndrome,pressure sores, pressure ulcers, pressure urticaria, pruritis, pruritusani, pseudofolliculitis barbae, psoriasis, PUPPP, purpura, pustules,pyogenic granuloma, rash, reactions to sunlight, rectal abscess, rectalfistula, rheumatic pain, ringworm, rosacea, roseola, rubella,salpingitis, scabies, scalded skin syndrome, scaling papular diseases,scarring, scleroderma, sebaceous cyst, seborrheic dermatitis, seborrheickeratoses, seborrheic keratosis, sexual arousal disorder, shingles, skinaging, skin cancer, skin neoplasia, skin neoplasms, skin rash, skintags, skin ulcers, sports injuries, squamous cell carcinoma,staphylococcal scalded skin syndrome, stasis dermatitis, Stevens-Johnsonsyndrome, sun spots, sunburn, thermal burns, tinea corporis, tineacruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis,trauma or injury to the skin, Trichomonas vaginalis, trichomoniasis,vaginal cancer, vaginal dryness, vaginismus, varicella, zoster virus,viral skin infections, vitamin D deficiency, vitiligo, vulvar cancer,vulvar disorders, vulvar dystrophy, vulvar intraepithelial neoplasia(VIN), vulvar pain, vulvodynia, warts, water hives, wrinkles, xerosis,yeast skin infections, zoster

Likewise, the foamable composition of the present disclosure is suitablefor preventing or treating a disorder of a body cavity or mucosalsurface, e.g., the mucosa of the nose, mouth, eye, ear, respiratorysystem, vagina, urethra, or rectum. Non limiting examples of suchconditions include chlamydia infection, gonorrhea infection, hepatitisB, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts,bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale,lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscumcontagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvardisorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy,vulvar intraepithelial neoplasia (VTN), contact dermatitis, pelvicinflammation, endometritis, salpingitis, oophoritis, genital cancer,cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginaldryness, dyspareunia, anal and rectal disease, anal abscess/fistula,anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids,anal itch, pruritus ani, fecal incontinence, constipation, polyps of thecolon and rectum.

In an embodiment of the present disclosure, the composition is usefulfor the treatment of an infection. In one or more embodiments, thecomposition is suitable for the treatment of an infection, selected fromthe group of a bacterial infection, a fungal infection, a yeastinfection, a viral infection and a parasitic infection.

In an embodiment of the present disclosure, the composition is usefulfor the treatment of wound, ulcer and burn. This use is particularlyimportant since the composition of the present disclosure creates athin, semi-occlusive layer, which coats the damaged tissue, whileallowing exudates to be released from the tissue.

The composition of the present disclosure is also suitable foradministering a hormone to the skin or to a mucosal membrane or to abody cavity, in order to deliver the hormone into the tissue of thetarget organ, in any disorder that responds to treatment with a hormone.

In one embodiment the disorder is an inflammation, skin inflammation,acne, rosacea, actinic keratosis, skin cancer, a local pain, joint painand osteoarthritis; the active agent is a nonsteroidal anti-inflammatorydrug, given at a therapeutically effective concentration.

In light of the hygroscopic nature of the composition, it is furthersuitable for the treatment and prevention of post-surgical adhesions.Adhesions are scars that form abnormal connections between tissuesurfaces. Post-surgical adhesion formation is a natural consequence ofsurgery, resulting when tissue repairs itself following incision,cauterization, suturing, or other means of trauma. When comprisingappropriate protective agents, the foam is suitable for the treatment orprevention of post surgical adhesions. The use of foam, is particularlyadvantageous because foam can expand in the body cavity and penetrateinto hidden areas that cannot be reached by any other alternative meansof administration.

Cosmetic Use

In one or more embodiments, the composition may be used for cosmeticuse. For example it may be used as part of a cosmetic formulation toprevent a cosmetic disorder or to improve the skin. Alternatively it maybe used with cosmetic effect for example as a cosmetic remover. It canbe dispensed in small quantities as a foam targeted to a surface andapplied locally with mechanical force causing the foam to break.

Route of Administration

The formulations disclosed herein can be applied to the target site as afoam. In one or more alternative embodiments the formulations areprepared without propellant and are applied as a gel or ointment, forexample, with the tetracycline as a suspension. Application can behourly, 2 hourly, 3 hourly, four hourly, six hourly or eight hourly,twelve hourly, daily, alternate-day or intermittent, as necessary. Forreasons of compliance less frequent applications, where possible arepreferable such as twice-daily or daily single applications. In caseswhere prolonged or long term treatment is required a higher initial doseis provided followed by a gradual reduction to a lower maintenance dose,which can be increased if further outbreaks occur.

The formulations are suitable for administration directly or indirectlyto an inflicted area, in need of treatment, through the following routesof administration:

-   1. Topical administration: for local effect, it is applied directly    where its action is desired;-   2. Enteral: when the desired effect is systemic (non-local), it is    given via the digestive tract; and-   3. Parenteral: when the desired effect is systemic, it is given by    other routes than the digestive tract

The following list more specifically exemplifies some routes ofadministration.

1. Topical

Topical administration is any form of administration that reaches a bodyorgan topically, such as epicutaneous administration (application ontothe skin), inhalation, enema, eye drops (onto the conjunctiva), eardrops, intranasal (into the nose) and vaginal.

Exemplary dosage forms that are suitable for topical administration ofthe stable formulations, such as tetracycline formulations includecream, gel, liniment, lotion, ointment, paste, spray, foam, mousse,lacquer (e.g., for nail treatment) and transdermal patch. Additionally,topical vaginal dosage forms may include a douche, an intrauterinedevice, a pessary (vaginal suppository), a vaginal ring and a vaginaltablet. Rectal dosage forms include enema and suppositories. Inhaleddosage forms include aerosol inhalers, metered dose inhalers andsolutions for nebulizer. Ophthalmic dosage forms include eye drop(solution or suspension), ophthalmic gel and ophthalmic ointment. In apreferred embodiment the dosage form is a foam that is thermally stableand breakable under shear force but is not “quick breaking” which allowscomfortable application and well directed administration to the targetarea,

2. Enteral

Enteral is any form of administration that involves any part of thegastrointestinal tract by mouth (orally), as buccal or sublingualtablets, capsules, suspensions, solutions, powder or drops; by gastricfeeding tube, duodenal feeding tube, or gastrostomy; and rectally, insuppository or enema form.

3. Parenteral by Injection or Infusion

Intravenous (into a vein); intraarterial (into an artery); intramuscular(into a muscle); intracardiac (into the heart); subcutaneous (under theskin); intraosseous infusion (into the bone marrow); intradermal, (intothe skin itself); intrathecal (into the spinal canal); andintraperitoneal (into the peritoneum).

4. Other Parenteral

Transdermal (diffusion through the intact skin); transmucosal (diffusionthrough a mucous membrane), e.g. insufflation (snorting), sublingual,buccal (absorbed through cheek near gumline) and vaginal; andinhalational; epidural (synonym: peridural) (injection or infusion intothe epidural space); and intravitreal.

EXAMPLES

The invention is described with reference to the following examples, ina non-limiting manner. The following examples exemplify the foamablecompositions and methods described herein. The examples are for thepurposes of illustration only and are not intended to be limiting. Manyvariations will suggest themselves and are within the full intendedscope.

Example 1 General Manufacturing Procedures

The following procedures are used to produce the foam samples describedin the examples below, in which only the steps relevant to eachformulation are performed depending on the type and nature ofingredients used.

Step 1: Hydrophobic solvents such as mineral oils are mixed at roomtemperature. Others solvents such as silicones, if present, are added atroom temperature under mixing until formulation homogeneity is obtained.

Step 2: The formulation is warmed to 70-80° C. and solid compounds suchas fatty alcohols, fatty acids and waxes are added and mixed untilcomplete dissolution.

Step 3: The formulation is cooled down to 30-40° C. and active agents ifpresent, and water if present are added under mixing until formulationhomogeneity is obtained.

Step 4: The formulation is packaged in aerosol canisters which arecrimped with a valve, pressurized with propellant and equipped with anactuator suitable for foam dispensing. Optionally a metered dosage unitcan utilized, to achieved delivery of repeatable measured doses of foam.

Materials

TABLE 1 Exemplary possible ingredients suitable for the production offoamable compositions disclosed herein. Equivalent materials from othermanufacturers can also be used satisfactorily. Chemical Name FunctionCommercial Name Supplier 1,3-Butandiol Solvent Butylene GlycolSigma-Aldrich Aluminum Starch Octenylsuccinate Absorbent Aluminum StarchNational Starch Octenylsuccinate Alpha-tocopherol AntioxidantAlpha-tocopherol Sigma-Aldrich Beeswax white Foam adjuvant Beeswax whiteHenry Lamotte Behenyl alcohol Foam adjuvant Lanette 22 Cognis Benzylalcohol Preservative Benzyl alcohol emprove Merck Betamethasone21-valerate Active agent Betamethasone 21-valcrate BP commissionlaboratory BHA Antioxidant Butylhydroxyanisole Merk BHT AntioxidantButylated Hydroxitoluene Spectrum C12-15 Alkyl Lactate Emollient C12-15Alkyl Lactate A&E Connock Calcitriol Active agent Calcitriol SolvayPharmaceutical BV Castor oil Solvent Castor oil Fluka Ceteareth-20Surfactant Sympatens acs 200G Colb Cetearyl alcohol & coconut alcoholSurfactant Montanov S Seppic Cetearyl octanoate Solvent Luvitol EHO BASFCeteth-2 Surfactant Lipocol C-2 Lipo Cetostearyl alcohol Foam adjuvantSpeziol C16-C18 Cognis Cetyl alcohol Foam adjuvant Speziol C16 CognisCholesterol Wax Cholesterol Spectrum Cocoglycerides Solvent Novata ACognis Coconut oil Solvent Coconut oil Henry Lamotte Cyclomethicone-5Solvent ST-cyclomethicone-5 Dow Diethylene glycol monoethyl SolventTranscutol Gattefosse ether Diisopropyl adipate Solvent IsoadipateSymrise GmbH Dimethyl Isosorbide Solvent Dimethyl Isosorbide DotticonDimethyl Sulfoxide Solvent Dimethyl Sulfoxide Fluka Doxycycline HyclateActive agent Doxycycline Hyclate Yangzhou Ethanol Absolute SolventEthanol Absolute J. T. Baker Ethylcellulose Polymer EC-Ethocel 100 cP FPColorcon Dow Gelled mineral oil Solvent Versagel M 750 Penreco GlycerinSolvent Glycerin Cognis Glyceryl monostearate Surfactant Cutina GMS V PHCognis Hard Fat Wax Softisan 378 Sasol Heavy Mineral Oil SolventParaffin oil liquid heavy Gadot Hexylene Glycol Solvent Hexylene GlycolSigma-Aldrich Hydrogenated castor oil Foam adjuvant Cutina HR CognisIsododecane Solvent AB117128 ABCR GmbH & Co. KG Isopropyl myristateSolvent Isopropyl Myristate Ph. Cognis Isostearic acid Foam adjuvantIsostearic acid Stearinerie Dubois Isostearyl alcohol Solvent Prisorine3515 Croda Lanolin Foam adjuvant Lanolin Spectrum Laureth-4 SurfactantDehydol LS 4 DEO N Cognis Light Mineral Oil Solvent Pioner 2076P Hansen& Rosenthal MCT Oil Solvent Captex 355 Abitec Menthol Additive MentholPremium Ingredients Int. Methyl glucose sesquistearate Surfactant TegoCare PS Evonik Goldeshmidt Metroidazole Active agent MetroidazoleGaldetma Minocycline HCl Active agent Minocycline HCl Hovione MometasoneFuroate Active agent Mometasone Furoate Sicor de Mexico Myristyl alcoholFoam adjuvant Speziol C14 Cognis Naproxen Active agent OctyldodecanolSolvent Eutanol G Cognis Oleth-20 Surfactant Emulgin O 0 S Cognis Oleylalcohol Solvent HD Eutanol V PH Cognis Oleic acid Solvent Oleic acidSpectrum Palmetic acid Foam adjuvant Edenor C16 98-100GW Cognis Paraffinwax 42-44 Wax Paraffin 42-44 Merck Paraffin wax 51-53 Wax Paraffin 51-53Merck Paraffin wax 58-62 Wax Paraffin 58-62 Merck PEG-100 StearateSurfactant Myrj 59 P Croda PEG-150 distearate Surfactant Emulgin EO 33Cognis PEG-40 Hydrogenated castor oil Surfactant Emulgin HRE 40 CognisPEG-40 Stearate Surfactant Myrj 52 S Croda PEG-75 Lanolin SurfactantSOLULAN 75 Lubrizol Polyethylene glycol-200 Solvent PEG 200 MerckPolyethylene glycol-400 Solvent PEG 400 Sigma-Aldrich Polysorbate 20Surfactant Tween 20 Merck Polysorbate 60 Surfactant Tween 60 Merck PPG15 stearyl ether Solvent Arlamol E Uniqema PPG-20 Methyl Glucose EtherHumectant Glucam P20 Distearate Lubrizol Distearate PPG-20-methylglucose ether Humectant Glucam P-20 Lubrizol Progesterone Active agentProgesterone Changzhou jiaerke pharmaceuticals Propane/Isobutane/Butane(20:78:2) Propellant A-46 Aeropress Propane/Isobutane/Butane PropellantAP-70 Aeropress (55:18:27) Propyl gallate Antioxidant Propyl gallateSigma-Aldrich Propylene glycol Solvent Propylene glycol Gadot Silica,Surface modified Dispersant Aerosil R 972 PH Evonik-Goldschmidt GmbHSorbitan monopalmitate Surfactant SPAN 40 Spectrum Sorbitan monostearateSurfactant SPAN 60 Uniqema Sorbitan monooleate Surfactant SPAN 80Spectrum Sorbitan sesquistearate Surfactant Tego care PS Degussa Soybeanoil Solvent Soybean oil Spectrum Steareth-2 Surfactant Brij 72 SpectrumSteareth-21 Surfactant Brij 721 Spectrum Stearic acid Foam adjuvantEdenol ST1M Cognis Stearyl Alcohol Foam adjuvant Speziol C18 CognisSucrose stearic acid estersD1803 Surfactant Surfhope SE D1803 MitsubishiSucrose stearic acid estersD1807 Surfactant Surfhope SE D1807 MitsubishiSucrose stearic acid estersD1811 Surfactant Surfhope SE D1811 MitsubishiSucrose stearic acid estersD1813 Surfactant Surfhope SE D1813 MitsubishiTerbinafine HCl Active agent Terbinafine HCl Taro Titanium dioxide —Kemira AFDC Kermira White Petrolatum (hard) Carrier Vaseline codex GALAiglon White Petrolatum (soft) Carrier Sofmetic LMF MMPCanisters Filling and Crimping

Each aerosol canister is filled with the pre-foam formulation (“PFF”,i.e., foamable carrier) and crimped with valve using vacuum crimpingmachine. The process of applying a vacuum will cause most of the oxygenpresent to be eliminated. Addition of hydrocarbon propellant may,without being bound by any theory, further help to reduce the likelihoodof any remaining oxygen reacting with the active ingredient. It may doso, without being bound by any theory, by one or more of dissolving in,to the extent present, the oil or hydrophobic phase of the formulation,by dissolving to a very limited extent in the aqueous phase, bycompeting with some oxygen from the formulation, by diluting out anyoxygen, by a tendency of oxygen to occupy the dead space, and by oxygenoccupying part of the space created by the vacuum being the unfilledvolume of the canister or that remaining oxygen is renderedsubstantially ineffective in the formulation.

Pressurizing & Propellant Filling

Pressurizing is carried out using a hydrocarbon gas or gas mixture.Canisters are filled and then warmed for 30 seconds in a warm bath at50° C. and well shaken immediately thereafter.

TESTS

By way of non-limiting example the objectives of hardness, collapse timeand freeze-thaw cycle (“FTC”) stability tests are briefly set out belowas would be appreciated by a person of skill in the art.

Collapse Time

Collapse Time, which is the measure of thermal stability, is examined bydispensing a given quantity of foam and photographing sequentially itsappearance with time during incubation at 36° C. The collapse timeresult is defined as the time when the foam height reaches 50% of itsinitial height or if the foam has not yet reached 50% of its initialheight after say 180 seconds then the collapse time is recorded asbeing >180. By way of illustration one foam may remain at 100% of itsinitial height for three minutes, a second foam may reach 90% of itsinitial height after three minutes, a third foam may reach 70% of itsinitial height after three minutes, and a fourth foam may reach 51% ofits initial height after three minutes, nevertheless in each of thesefour cases the collapse time is recorded as >180 seconds since forpractical purposes for easy application by a patient to a target themajority of the foam remains intact for more than 180 seconds. If thefoam for example reaches 50% of its original height after say 100seconds it would be recorded as having a collapse time of 100 seconds.It is useful for evaluating foam products, which maintain structuralstability at skin temperature for at least 1 minute. Foams which arestructurally stable on the skin, for at least one minute are termed“short, term stable” carriers or foams.

Alternatively, a Simple Collapse Time can be assessed by placing a foamsample on the warm fingers of a volunteer and measuring the time ittakes to melt on the fingers.

Density

In this procedure, the foam product is dispensed into vessels (includingdishes or tubes) of a known volume and weight. Replicate measurements ofthe mass of foam filling the vessels are made and the density iscalculated. The canister and contents are allowed to reach roomtemperature. Shake the canister to mix the contents and dispense anddiscard 5-10 mL. Then dispense foam into a pre-weighed tube, filling ituntil excess is extruded. Immediately remove (level off) excess foam atboth ends and weigh the filled tube on the weighing balance.

Viscosity

Viscosity is measured with Brookfield LVDV-H+ PRO with spindle SC4-25 atambient temperature and 10, 5 and 1 RPM. Viscosity is usually measuredat 10 RPM. However, at about the apparent upper limit for the spindle of˜>50,000 CP, the viscosity at 1 RPM may be measured, although thefigures are of a higher magnitude. Unless otherwise stated viscosity ofthe pre-foam formulation (PFF) is provided. It is not practical to tryand measure the viscosity of the foamable formulation with regularpropellants since they have to be stored in sealed pressurized canistersor bottles. In order to simulate the viscosity in the foamableformulations with propellant an equivalent weight of pentane (a lowvolatile hydrocarbon) is added to and mixed with the pre-foamformulation and left overnight. The viscosity is then measured as above.

FTC (Freeze Thaw Cycles)

Foam appearance under extreme conditions of repeated heating and coolingis evaluated by cycling through cooling, heating, (first cycle) cooling,heating (second cycle) etc., conditions, commencing with −10° C. (24hours) followed by +40° C. (24 hours) and measuring the appearancefollowing each cycle. The cycle is repeated for up to three times.

Chemical Stability

The amount of active agent present is analyzed chromatographically infoam released from various pressurized canisters. Analysis is carriedout at baseline and at appropriate time intervals thereafter. Thecanisters are typically stored in controlled temperature incubators atone or more of 5° C., 25° C. and 40° C. At appropriate time intervalscanisters are removed and the amount of active agent in the foam sampleis measured.

Bubble Size

Foams are made of gas bubbles entrapped in liquid. The bubble size anddistribution reflects in the visual texture and smoothness of the foam.Foam bubbles size is determined by dispensing a foam sample on a glassslide, taking a picture of the foam surface with a digital camera,equipped with a macro lens. The diameter of about 30 bubbles is measuredmanually relatively to calibration standard template. Statisticalparameters such as mean bubble diameter, standard deviation andquartiles are then determined. Measuring diameter may also be undertakenwith image analysis software. The camera used was a Nikon D40X Camera(resolution 10 MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mmF2.8 EX DCs HSM). Pictures obtained are cropped to keep a squared regionof 400 pixels×400 pixels.

Shakability

Shakability represents she degree to which the user is able to feel/hearthe presence of the liquid contents when the filled pressurized canisteris shaken. Shaking is with normal mild force without vigorous shaking orexcessive force. When the user cannot sense the motion of the contentsduring shaking the product may be considered to be non-shakable. Thisproperty may be of particular importance in cases where shaking isrequired for affecting proper dispersion of the contents.

Table of Shakability scoring Good shakability (conforms to required 2quality specification) Moderate shakability (conforms to required 1quality specification) Not shakable (fails to meet required quality 0specification) but may still be flowable and allow foam formation ofquality Is substantially not able to pass through valve BlockAging by Centrifugation:

-   1. Principle of test

The centrifugation used in this procedure serves as a stress conditionsimulating the aging of the liquid formulation under investigation.Under these conditions, the centrifugal force applied facilitatescoalescence of dispersed globules or sedimentation of dispersed solids,resulting in loss of the desired properties of the formulation.

-   2. Procedure-   2.1. Following preparation of the experimental formulation/s, allow    to stand at room temperature for ≥24 h (hour).-   2.2. Handle pentane in a chemical hood. Add to each experimental    formulation in a 20-mL glass vial a quantity of pentane equivalent    to the specified quantity of propellant for that formulation, mix    and allow formulation to stand for at least 1 h and not more than 24    h.-   2.3. Transfer each mixture to 1.5 ml microtubes. Tap each microtube    on the table surface to remove entrapped air bubbles.-   2.4. Place visually balanced microtubes in the centrifuge rotor and    operate the centrifuge at say 1,000 rpm for 5 min or 10 min. The    centrifuge can be a BHG HEMLE Z 231 M.-   2.5. Centrifugation can also be executed at a higher rpm for a    shorter period or a lower rpm for a longer period bearing in mind    the G-force experienced by the formulations is many fold greater    than the one G to which a formulation would be exposed to during its    shelf life. Centrifugation can also be executed at a higher rpm for    the same period, say 3000 or 10,000 rpm to simulate an extremely    high stress level.    Penetration

Transdermal penetration of Minocycline was tested using the Franz cellin-vitro diffusion system. This system is commonly used to test thedelivery of drugs through the skin from semisolid topical dosage forms.Pig skin was used according to the OECD Draft, New Guideline 428, sincepig skin shows similar permeation characteristics to human skin. Thefollowing experimental parameters were employed:

-   1. Two formulations were tested: 244 foam, with 1% minocycline and    244 foam with 4% minocycline. The two carrier formulations were    unchanged accept that the amount of mineral, oil was reduced by 3%    to allow for the increase in minocycline.-   2. Vertical Franz diffusion cells were used (PermeGear, 1.77 cm²    area, 14 ml receptor fluid).-   3. 6 cells were used to test the 4% formulation, 5 cells were used    to test the 1% formulation and one cell was used as a “negative    control” (without any applied sample). Approximately 500 mg of    product was placed in each cell. [Note the amount per skin area was    calculated to be about three times more than an amount that might be    applied clinically, namely for 244 with 4% minocycline 300 mg by    weight of foam product which comprises about 12 mg of minocycline.]-   4. The receiving compartments were sampled at baseline and 3, 6, 9    and 24 hours following application. At the 24 hours time point the    skin was processed as follows:    -   Residues of materials were removed from the skin using filter        paper, followed by stripping the skin once using adhesive tape        “Scotch Magic® Tape”, 3M.    -   Sequential 19 tapes (9 and 10) were transferred into two        separate vials with 3 mL extraction solution (“Stratum Corneum        1” and “Stratum Corneum 2”).    -   The circular skin area (1.77 cm2) was cut and transferred to a 3        mL extraction solution (Viable skin—VS samples) vial.-   5. The amount of active agent present was analyzed    chromatographically: About 1 g of foam or pre-foam formulation is    dissolved in 25 mL while mixing. The sample solution is filtered    with PTFE 0.2 μm filter. The filtrate is analyzed by UPLC using a    C-18 column; elution is performed with a mobile phase containing    0.1M Ammonium oxalate:0.01M EDTA:DMF:THF, 60:18:12:8(v/v). Note DMF    is dimethylformamide and THF is tetrahydrofurane. The content of MCH    and of 4-Epimer is calculated using the ratio between MCH peak area    response in the sample solution and the average response area of MCH    peak in the working standard solution present at a similar    concentration.    Residence on the Skin

The degradation of active pharmaceutical ingredient, namely, minocyclinewas assessed following exposure to pig skin. Formulation 232A,containing 1% minocycline was applied to freshly retrieved porcinedermatomated skin and samples of the foam were analyzedchromatographically for both minocycline and a known 4-Epi degradationproduct at the start and then after 1, 3 and 6 hours of exposure.

Microbiological Tests

-   -   a) Microbial load: Testing was performed according to EP 2.6.12        and 2.6.13 as described in the European Pharmacopea.    -   b) Preservative efficacy: Testing was performed according to USP        <51> and EP 5.6, 2007 5.1.3. as described in the European and        U.S. Pharmacopea.

The test consists of challenging the product with specifiedmicroorganisms, storing the inoculated preparations at a prescribedtemperature, removing the inoculated samples at specified intervals oftime and counting the number of viable organisms in the withdrawnsamples using a plate-count procedure. Formulations were challenged byintroducing the following microorganisms:

-   -   Escherichia coli (ATCC no. 8739)    -   Staphylococcus aureus (ATCC no. 6538)    -   Pseudomonas aeruginosa (ATCC no. 9027)    -   Candida albicans (ATCC no. 10231)    -   Aspergillus niger (ATCC no. 16404)

The number of colony-forming units (cfu/g) determined at each incubationtime point was compared to the number of cfu/g measured innon-inoculated control samples. In order to verify that the samplestested are free of microbial contaminants, the microbial load(base-line) in the samples was determined prior to preservative efficacytesting. Study results are expressed as the number of survivingmicroorganisms (cfu/g).

-   -   c) Water Activity (Aw): The test for water activity was        performed on pre-foam formulation samples introduced into the        measuring cell of a PAWKIT water activity meter from DECAGON.    -   d) In-vitro effect on microbial growth: The tested microorganism        is grown on Tryptic Soy Agar Slants. After incubation, the        bacteria is harvested using sterile buffer phosphate pH 7.0, to        obtain a microbial count, of about 10⁴ cfu/ml. 0.2 ml of the        above suspension is spread on Letheen Agar plate and put aside        to dry for 20 minutes at room temperature. A sterile disc of 6        mm diameter which has been soaked in 10 μl of the tested        antibacterial pre-foam-formulation (PFF) is put on the microbial        film, the plate is incubated at 35° C. for 1-2 days. A control        experiment is also performed where no antibacterial material is        put on the sterile discs. Antimicrobial activity of the tested        material inhibits growth of the microorganism around the disc,        leaving a transparent zone around it. The diameter of the        inhibition zone is measured in mms.        HET-CAM

The potential of compounds to cause irreversible or severe eyeirritation or corrosion may be detected by observing adverse changes,which occur in the chorioallantoic membrane (CAM) of the egg afterexposure to test chemicals. The methodology is described in Example 17.

Apoptosis

UVB irradiation of the skin is known inter alia to increase epidermalcell apoptosis. Specimens are treated topically then irradiated with UVBand incubated. Apoptosis activation is measured post-irradiation bymeasuring the extent of caspase 3 activity. The methodology is describedin Example 18.

Compatibility

Active agent is incubated with various excipients at one or moretemperatures for a certain fixed period or to the point wheredegradation was suspected. Visual inspection is a criterion forindication of compatibility. Any change of color indicates oxidation ordegradation. The methodology is described in Example 19.

Color/Pigmentation

Samples are applied to fair healthy human skin to observe whether anyskin pigmentation occurs. The skin is observed prior to and followingapplication. The methodology is described in Example 20.

Section A—Carrier Compositions Example 2 Non Surfactant Oleaginous FoamFormulations

Surface active agents are known to be useful foaming agents, and thus itis not obvious to produce good quality foams free of surfactants. Asshown table 2 below, formulations 001 and 002 containing a mixture ofheavy mineral oil and light mineral oil with or without cyclomethiconefail to produce foams and release only liquids from the pressurizedcanisters. Compounds other than customary surfactants have beenidentified below that are suitable for the foaming of oleaginousvehicles.

TABLE 2 Oleaginous Compositions Formulations 001 002 % w/w % w/wIngredients Heavy mineral oil 75.00 70.00 Light mineral oil 25.00 75.00Cyclomethicone — 5.00 Total 100.00 100.00 Propellant A46 12.00 12.00Results Foam quality Poor Poor

Silicone oils such as cyclomethicone are included in the formulationsprimarily as cosmetic agent, for their contribution to skin feelingproperties. Volatile cyclomethicones can help reduce the greasy skinfeeling that may be present in oleaginous formulations.

Example 3 Oleaginous Formulations Containing a Fatty Acid

Two fatty acids were used in combination with heavy mineral oil, lightmineral oil and cyclomethicone, and tested for their foaming properties.As described in Table 3 below, formulation 003 containing isostearicacid (a liquid fatty acid) did not give rise to foam but merelygenerated bubbly liquids. Formulation 004 containing stearic acid (asolid fatty acid) initially produced a fairly good quality foam, butwhich was not stable and collapsed after 10 seconds. It follows thatthat fatty acids alone are not sufficient as foaming agents inoleaginous formulations even in reasonably high amounts. Also, theaverage bubble size was quite large and more than double that of aquality foam.

TABLE 3 Oleaginous compositions containing a fatty acid Formulations 003004 % w/w % w/w Ingredients Heavy mineral oil 60.00 60.00 Light mineraloil 25.00 25.00 Cyclomethicone 5.00 5.00 Stearic acid (C18) — 10.00Isostearic acid (C18) 10.00 — Total 100.00 100.00 Propellant A46 12.0012.00 Results Foam quality Fair Fairly Good Collapse Time (sec) 10 10Foam density (/mL) — 0.071 Bubble size (micrometers) — 245 PFF Viscosity(cP) 58 1442

Example 4 Oleaginous Compositions Containing Fatty Alcohols

The influence of fatty alcohols on the foaming properties of oleaginousformulations was studied. Several fatty alcohols of different chainlength were used in combination with heavy mineral oil, light mineraloil and cyclomethicone, and checked for their foaming properties. Asdescribed in Table 4 below, formulations 005, 006 and 007 respectivelycontaining myristyl alcohol, cetyl alcohol or stearyl did not give riseto quality foams but merely generated bubbly liquids of fair qualityfoam that quickly collapsed. Formulation 009 which contains behenylalcohol (a fatty alcohol having 22 carbons) produced fairly good qualityfoams that quickly collapsed. It follows that fatty alcohols alone arenot sufficient as foaming agents in oleaginous formulations.

TABLE 4 Oleaginous compositions containing various fatty alcoholsFormulations 005 006 007 009 % w/w % w/w % w/w % w/w Ingredients Heavymineral oil 60.00 60.00 60.00 60.00 Light mineral oil 25.00 25.00 25.0025.00 Cyclomethicone 5.00 5.00 5.00 5.00 Myristyl alcohol (C14) 10.00 —— — Cetyl alcohol (C16) — 10.00 — — Stearyl alcohol (C18) — — 10.00 —Behenyl alcohol (C22) — — — 10.00 Total 100.00 100.00 100.00 100.00Propellant A46 12.00 12.00 12.00 12.00 Results Foam quality Fair FairFair Fairly Good Collapse Time (sec) 10 10 10 10 Foam density (/mL) — —— 0.160 Bubble size (micrometers) — — — 125 PFF Viscosity (cP) 206 938585 3839

Example 5 Oleaginous Formulations Containing a Combination of FattyAcids and Fatty Alcohols

Formulations were prepared, containing a combination of fatty acids andfatty alcohols and checked for their foaming properties. As described inTable 5a below, formulations 010 (containing stearic acid and myristylalcohol) and formulation 0.17 (containing isostearic acid and stearylalcohol) did not give rise to quality foams but merely generated bubblyliquids.

However, very surprisingly, the combination of stearic acid with cetylalcohol, stearyl alcohol, cetostearyl alcohol or behenyl alcohol giverise to good quality foams having a fine bubble structure as shown informulations 011, 012, 013 and 014. Such foams can be successfullyproduced in the presence or in the absence of silicone oils, as shown informulation 011 and 016, despite the defoaming effect of silicones.Moreover, formulations 012 and 014 containing a combination of stearicacid with stearyl alcohol or behenyl alcohol give rise to stable foamswhich did not collapse after 180 sec at 36° C. Thus, it has beendiscovered that a combination of fatty alcohols and fatty acids has asynergistic effect and possesses effective foaming properties in thecase of oleaginous compositions to achieve a thermally stable breakablefoam. Interestingly cetyl and stearyl alcohol achieved the lowestaverage bubble size, whilst using a combination of the two led to asubstantial reduction in viscosity of the pre foam formulation.

TABLE 5a Oleaginous compositions containing various Fatty Acids andFatty Alcohols Formulation 010 011 012 013 014 015 016 017 Ingredients %w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w Heavy mineral oil 60.0060.00 60.00 60.00 60.00 57.00 60.00 60.00  Light Mineral oil 25.00 25.0025.00 25.00 25.00 25.00 30.00 25.00  Cyclomethicone 5.00 5.00 5.00 5.005.00 5.00 — 5.00 Myristyl alcohol 5.00 — — — — 3.00 — — Cetyl alcohol —5.00 — — — — — — Stearyl alcohol — — 5.00 — — 5.00 5.00 5.00 Cetostearylalcohol — — — 5.00 — — — — Behenyl alcohol — — — — 5.00 — — — Isostearicacid — — — — — — — 5.00 Stearic acid 5.00 5.00 5.00 5.00 5.00 5.00 5.00— Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Propellant A46 12.00 12.00 12.00 12.00 12.00 — 12.00 12.00  PropellantAP-70 — — — — — 8.00 — — Results Foam quality Fair Good Good Good GoodGood Good Fair Collapse Time (sec) 10 30 >180 30 >180 >180 >180 10  Foam density (g/mL) — 0.142 0.157 0.210 0.139 0.082 0.100 — Bubble size(micrometers) — 60 74 137 139 — — — PFF Viscosity (cP) 107 22763 23866107 5023 18987 — —

Formulations were prepared, containing various ratios of fatty acids tofatty alcohols and checked for their foaming properties, as described inTable 5b.

TABLE 5b Oleaginous compositions containing various Fatty Acids andFatty Alcohols ratios Formulations 215 213 211 212 214 % w/w % w/w % w/w% w/w % w/w Ingredients Heavy 65.0 65.0 65.0 65.0 65.0 Mineral oil Light25.0 25.0 25.0 25.0 25.0 Mineral oil Stearyl 1.50 3.33 5.00 6.66 8.50alcohol Stearic acid 8.50 6.66 5.00 3.33 1.50 Total 100.0 100.0 100.0100.0 100.0 Propellant 10.0 10.0 10.0 10.0 10.0 AP-70 Results Foam GoodGood Ex- Good- Fairly Quality cellent Good Collapse >180 >180 >180 >180— Time (sec) Ratio fatty 3.17 1:2 1:1 2:1 (5.6:1) alcohol:fatty (1:5.6)17:3 acid

It was observed that in oleaginous foam formulations containing fattyalcohols and fatty acids, the ratio of the concentrations of fattyalcohol to fatty acid influenced the foaming properties. Foams of goodquality that did not collapse after 180 seconds at 36° C. were obtainedwith a ratio of fatty alcohol:fatty acid of 3:17 to 2:1. Foams ofexcellent quality were obtained when the ratio was 1:1. However, fairlygood foams were obtained with a ratio of 5.6:1. Thus, in one or moreembodiments the ratio of fatty alcohol to fatty acid is about 3:17 toabout 2:1; or about 1:6 to about 16:3; or about 1:7 to about 5:1 orbetween any first ratio to any second ratio.

Formulations were prepared, containing various concentrations of fattyacids and fatty alcohols with a fixed ratio of fatty alcohol to fattyacid of 1:1 and checked for their foaming properties, as described inTable 5c.

TABLE 5c Oleaginous compositions containing various Fatty Acids andFatty Alcohols concentrations Formulations 221 222 223 211 224 % w/w %w/w % w/w % w/w % w/w Ingredients Heavy Mineral oil 65.0 65.0 65.0 65.065.0 Light Mineral oil 32.5 30.0 28.0 25.0 20.0 Stearyl alcohol 1.252.50 3.50 5.00 7.50 Stearic acid 1.25 2.50 3.50 5.00 7.50 Total 100.0100.0 100.0 100.0 100.0 Propellant AP-70 10.0 10.0 10.0 10.0 10.0Results Foam Quality Fair Good Excellent Excellent Block Collapse Time(sec) — >180 >180 >180 —

It was observed that foams of good to excellent quality that did notcollapse after 180 seconds at 36° C. were obtained with a fixed ratio offatty alcohol to fatty acid of 1:1 and a total concentration of fattyalcohol together with fatty acid ranging from about 5% to about 10%. Fora total concentration of fatty alcohol together with fatty acid of 15%,the PFF content was very viscous and could not be expelled through thevalve. This can be overcome by including higher amounts of propellant,or propellant of higher vapor pressure or a low viscosity solvent suchas alkyl benzoate.

Example 6 Oleaginous Formulations Containing Fatty Alcohols, Fatty Acidsand Waxes

Formulations, containing a combination of fatty acids, fatty alcoholsand waxes were prepared and checked for their foaming properties. Asnoted in Table 6a below, formulations 018 containing fatty alcohols andlow amounts of stearic acid did not give rise to quality foams butgenerated fairly good quality foam that very quickly collapsed.Surprisingly, the addition of hydrogenated castor oil and beeswax (informulation 019) both of which are solid waxes at room temperature,enhanced the foam quality and good quality foam that was stable at 36°C. was obtained. Furthermore, formulations containing waxes feel lessgreasy upon application on skin. Thus, it has been discovered that waxesare useful foamer ingredients instead of fatty acids in oleaginous foamsfree of standard surfactants, and additionally they can enhance both theskin feeling and the foam quality.

TABLE 6a Oleaginous compositions containing waxes Formulations 018 019 %w/w % w/w Ingredients Heavy mineral oil 63.00 59.50 Light mineral oil25.00 25.00 Cyclomethicone 5.00 5.00 Hydrogenated castor oil — 1.50Beeswax — 2.00 Cetostearyl alcohol 2.50 2.50 Stearyl alcohol 1.50 1.50Behenyl alcohol 1.00 1.00 Stearic acid 2.00 2.00 Total 100.00 100.00Propellant A46 12.00 12.00 Results Foam quality Fairly Good GoodCollapse Time (sec) 10 120 Foam density (g/mL) — 0.207 Bubble Size(micrometers) 155 79

It is apparent that the addition of a wax to the composition improvedthe foam quality from fairly-good (insufficient) to good (acceptable)and collapse time from 10 (unacceptable) to 120 seconds (acceptable).

Additional formulations were prepared, containing waxes alone and incombination with a fatty acid or a fatty alcohol and checked for theirfoaming properties. As described in Table 6b below, formulations 021,021b and 022 containing beeswax alone or in combination withhydrogenated castor oil did not give rise to quality foams but merelygenerated bubbly liquids. Formulations 020 containing hydrogenatedcastor oil alone generated fairly good quality foam that collapsed after10 seconds. On the other hand the combination of beeswax, hydrogenatedcastor oil and fatty alcohol enhanced the foam quality and produced goodquality foam that were stable at 36° C. for more than 180 seconds, asshown in formulation 023. However, formulations 024 and 024b composed ofcombinations of beeswax, hydrogenated castor oil and fatty acid onlywithout fatty alcohol generated fairly good foam that quickly collapsed.This shows the importance of the presence of both fatty alcohols andwaxes in oleaginous foam compositions. Additionally, wax such ashydrogenated caster oil or beeswax can not only be used in place of afatty acid but it can be used to facilitate a lower level of fatty acidpresence without compromising the foam properties.

TABLE 6b Oleaginous compositions containing waxes Formulations 020 021021b 022 023 024 024b Ingredients % w/w % w/w % w/w % w/w % w/w % w/w %w/w Heavy mineral oil 60.00 60.00 60.00 60.00 60.00 60.00 60.00 Lightmineral oil 25.00 25.00 30.00 25.00 25.00 25.00 25.00 Cyclomethicone5.00  5.00 — 5.00 5.00 5.00 5.00 Hydrogenated castor oil 10.00 — — 5.002.50 2.50 5.00 Beeswax — 10.00 10.00 5.00 2.50 2.50 2.50 Stearyl alcohol— — — — 5.00 — — Stearic acid — — — — — 5.00 5.00 Total 100.00 100.00 100.00  100.00 100.00 100.00 100.00 Propellant A46 12.00 12.00 12.0012.00 12.00 12.00 12.00 Results Foam quality Fairly Fair Fair Fair GoodFairly Fairly Good Good Good Collapse Time (sec) 10 10   10   10 >180 1010

Formulations were prepared, containing various ratio of beeswax tohydrogenated castor oil, with a fixed concentration of fatty alcohol andchecked for their foaming properties, as described in Table 6c.

TABLE 6c Oleaginous compositions containing waxes in different ratiosFormulations 229 228 226 227 230 % w/w % w/w % w/w % w/w % w/wIngredients Heavy Mineral oil 65.0 65.0 65.0 65.0 65.0 Light Mineral oil25.0 25.0 25.0 25.0 25.0 Stearyl alcohol 5.00 5.00 5.00 5.00 5.00Beeswax 0.83 1.67 2.50 3.33 4.17 Hydrogenated castor oil 4.17 3.33 2.501.67 0.83 Total 100.0 100.0 100.0 100.0 100.0 Propellant AP-70 10.0 10.010.0 10.0 10.0 Results Foam Quality Fairly Good Fairly Good Good- GoodGood Collapse Time (sec) — — >180 >180 >180 Ratio Beeswax:Hydrog. 1:51:2 1:1 2:1 5:1 Castor oil

It was observed that in oleaginous foam formulations containing fattyalcohols and waxes such as beeswax and hydrogenated castor oil, theratio of the concentrations of beeswax to hydrogenated castor oilinfluenced foaming properties. Foams of good quality that did notcollapse after 180 seconds at 36° C. were obtained with a ratio ofbeeswax to hydrogenated castor oil of 1:1 or more, whereas fairly goodfoams were obtained when the level of the beeswax was less than 2% andthe amount of hydrogenated cater oil exceeded the level of beeswax.According to one or more embodiments there is provided a composition,wherein ratio of beeswax to hydrogenated castor oil is about or at least1:1. According to one or more other embodiments the ratio may be lessthan 1:1 where beeswax is more than about 2%.

Formulations were prepared, containing various ratio of fatty alcohol towax and checked for their foaming properties, as described in Table 6d.

TABLE 6d Oleaginous compositions containing waxes and fatty alcohols indifferent ratios Formulations 234 231 230 232 233 Ingredients % w/w %w/w % w/w % w/w % w/w Heavy Mineral oil 65.0 65.0 65.0 65.0 65.0 LightMineral oil 25.0 25.0 25.0 25.0 75.0 Beeswax 7.50 6.255 4.17 2.085 0.834Steatyl alcohol 1.00 2.50 5.00 7.50 9.00 Hydrogenated 1.50 1.245 0.830.415 0.166 castor oil Total 100.0 100.0 100.0 100.0 100.0 PropellantAP-70 10.0 10.0 10.0 10.0 10.0 Results Foam Quality Fair Good Good Good—Fair Foam Collapse Time — >180 >180 >180 — Ratio Fatty 1:9 2:3 1:1 3:29:1 alcohol:Wax

In the above experiment the ratio of beeswax to hydrogenated caster oilwas maintained at 5:1, whilst the amount of fatty alcohol wasprogressively increased. It was observed that in oleaginous foamformulations containing fatty alcohols and waxes, the ratio of theconcentrations of fatty alcohol to wax (beeswax plus hydrogenated casteroil) influenced foaming properties. Foams of good quality that did notcollapse after 180 seconds at 36° C. were obtained with a ratio of fattyalcohol to wax of 2:3 to 3:2 or more, whereas only fair foams wereobtained with a ratio of 1:9 or 9:1. So in one or more embodiments theratio of fatty alcohol to wax (total) is between about 2:3 to about 3:2;or between about 1:2 to about 2:1 or between about 1:3 to about 3:1; orbetween about 4:1 to about 1:4 or between any first ratio to any secondratio.

Example 7 Oleaginous Formulations Containing Various HydrophobicSolvents

Formulations were prepared, containing various hydrophobic solvents andchecked for their foaming properties. As described in Table 7 below,formulations containing substantial amounts of MCT oil (capric/caprylictriglycerides), octyldodecanol, coconut oil, PPG-15 stearyl ether andsoybean oil provided good quality foams that were stable at 36° C., asshown in formulation 025 and 026.

TABLE 7 Oleaginous compositions containing various oils Formulations 025026 Ingredients % w/w % w/w Light Mineral oil — 6.65 Cyclometicone 5.005.00 MCT oil 50.00 — Octyldodecanol 12.00 — Coconut oil — 25.00 PPG-15stearyl ether 15.00 — Soybean oil — 50.00 Lanolin — 2.00 Hydrogenatedcastor oil 2.00 2.00 Beeswax 2.50 2.00 Cetostearyl alcohol 2.50 2.50Stearyl alcohol 5.00 1.50 Behenyl alcohol 1.00 1.10 Aerosil (SiO2) —0.25 Stearic acid 5.00 2.00 Total 100.00 100.00 Propellant A46 12.0012.00 Results Foam quality Good Good Collapse Time (sec) 150 150 Foamdensity (g/mL) 0.293 0.167

Example 8 Foamable Oil Combinations with Fatty Acid, Fatty Alcohol andWax

Part A—Without Water

Foam formulations were prepared containing high amounts of oils, incombination with fatty alcohols, fatty acids and waxes, according to thegeneral manufacturing procedure described in Example 1. As described inTable 8a, quality breakable foams were obtained in compositionscontaining different oils. The pre-foam formulations were viscoussemi-solid primarily due to the addition of waxes and/or foam adjuvants.Upon addition of propellant, the formulations were shakable, indicatingthat the formulation within the aerosol canister is liquid.

TABLE 8a Foamable Oil Combinations with Fatty acid, Fatty alcohol andWax Formulations A6 A7 A8 A9 A10 Avocado oil 20.00 20.00 — — — Jojobaoil — — 20.00 30.00 20.00 Coconut oil 20.00 20.00 20.00 — — Mineral oil,light 20.00 — 20.00 16.00 7.00 Grapeseed oil 20.00 20.00 20.00 30.0030.00 Calendula oil — 10.00 5.00 — — Pomegrante — 10.00 — — — Seed oilPeanut oil — — — — 20.00 Cocoglyceride 3.00 3.00 — — — Beeswax 3.00 3.003.00 3.00 3.00 Stearic acid 2.00 2.00 2.00 2.00 2.00 Cetyl alcohol 3.003.00 3.00 4.00 4.00 Shea butter 2.00 3.00 — — — Behenyl alcohol 1.001.00 1.00 2.00 2.00 Paraffin wax 6.00 5.00 6.00 13.00 12.00 Total 100100 100 100 Propellant A70 10.00 10.00 10.00 10.00 10.00 Results FoamQuality Excellent Excellent Good Excellent ExcellentPart B—with Low Water (10% or 20%)

Foam formulations were prepared containing high amounts of oils, lowamounts of water, in combination with fatty alcohols, fatty acids andwaxes, according to the general manufacturing procedure described inExample 1. As described in Table 8b, quality breakable foams wereobtained in different compositions containing oils and low amounts ofwater, with or without fragrance. The pre-foam formulations were viscoussemi-solid primarily due to the addition of waxes and/or foam adjuvants.Upon addition of propellant, the formulations were shakable, indicatingthat the formulation within the aerosol canister is liquid.

TABLE 8b Foamable Oil Combinations with Water, Fatty acid, Fatty alcoholand Wax Formulations A11 A12 A13 Water 10.00 10.00 20.00 Avocado oil20.00 19.75 15.00 Coconut oil 20.00 20.00 20.00 Grapeseed oil 20.0020.00 20.00 Calendula oil 5.00 5.00 2.50 Pomegrante Seed oil 5.00 5.002.50 Cocoglyceride 3.00 3.00 3.00 Beeswax 3.00 3.00 3.00 Stearic acid2.00 2.00 2.00 Cetyl alcohol 3.00 3.00 3.00 Shea butter 3.00 3.00 3.00Behenyl alcohol 1.00 1.00 1.00 Paraffin wax 5.00 5.00 5.00 Fragrance(FC10618) — 0.25 — Total 100 100 100 Propellant A70 10.00 10.00 10.00Results Foam Quality Excellent Excellent Excellent Foam Density (g/mL)0.240 — 0.224 Collapse time at 36° C. (sec) >180 — >180 Centrifugationat 1000 rpm 20% creaming — 20% creaming 5% separation 5% separation

Surprisingly, and despite the absence of surfactants, water-in-oilemulsion formulations were prepared containing high amounts of oils andlow amounts of water, in combination with fatty alcohols, fatty acidsand waxes, which produced quality breakable foams.

In one or more embodiments, there is provided, a foamable formulationcomprising high amounts of hydrophobic solvents, low amounts of water,fatty alcohols, fatty acids and waxes, wherein the formulation generatesquality breakable foam which does not collapse for more than 180 secondsat 36° C. In one or more embodiments, the amount of water is lower thanabout 20%. In one or more embodiments, the amount of water is lower thanabout 10%. In one or more embodiments, the amount of water is lower thanabout 5%. In one or more embodiments, the amount of water is lower thanabout 2%. In one or more embodiments, the oleaginous formulation isessentially free of water.

Example 9 Petrolatum Based Foamable Compositions

Foam formulations were prepared containing high amounts of Petrolatum,in combination with liquid oils, fatty alcohols and waxes, according tothe general manufacturing procedure described in Example 1. As describedin Table 9a, quality breakable foams were obtained in differentcompositions containing Petrolatum. The pre-foam formulations wereviscous semi-solid. Upon addition of propellant, the formulations wereshakable, indicating that the formulation within the aerosol canister isliquid.

TABLE 9a Oleaginous Formulations containing Petrolatum Formulations A1A2 A3 A8 White petrolatum 70.00 50.00 50.00 91.00 Grape seed oil — 15.00— — Jojoba oil 15.00 15.00 15.00 — Mineral oil 5.00 9.00 10.00 — Wheatgerm oil — — 15.00 — Paraffin wax 51-53 — 2.00 5.00 — Beeswax 1.00 1.00— 1.00 Cetostearyl alcohol 4.00 4.00 4.00 4.00 Hydrogenated castor oil3.00 2.00 — 3.00 Cyclomethicone 5-NF 1.00 1.00 — — Behenyl alcohol 1.001.00 1.00 1.00 Total 100 100 100 100 Propellant A70 10.00 10.00 10.0010.00 Results Foam Quality Excellent Excellent Excellent Excellent FoamDensity (g/mL) 0.159 0.154 0.175 0.226 Collapse time at 36°C. >180 >180 >180 >180 (sec) Mean Bubble size — — 150 — (micrometers)

In one or more embodiments, there is provided a foamable formulationcomprising Petrolatum, optionally a liquid oil, a fatty alcohol and awax, wherein the formulation generates quality breakable foam.

Foam formulations were also prepared without waxes, containing highamounts of Petrolatum, in combination with liquid oils and fattyalcohols, according to the general manufacturing procedure described inExample 1. As described in Table 9b, quality breakable foams wereobtained in different compositions containing Petrolatum without waxes.The pre-foam formulations were viscous semi-solid. Upon addition ofpropellant, the formulations were shakable, indicating that theformulation within the aerosol canister is liquid.

TABLE 9b Oleaginous Formulations containing Petrolatum Formulations A4A5 A6 A7 White petrolatum 50.00 70.00 70.00 75.00 Wheat germ oil — 10.00— — Jojoba oil — 5.00 — — Avocado oil 15.00 — — — Coconut oil 15.00 — —— Mineral oil 10.00 3.00 20.00 20.00 Shea butter 5.00 5.00 5.00 —Cetostearyl alcohol 4.00 4.00 4.00 4.00 Cyclomethicone 5-NF — 2.00 — —Behenyl alcohol 1.00 1.00 1.00 1.00 Total 100 100 100 100 Propellant 7010.00 10.00 10.00 10.00 Results Foam Quality Good Excellent ExcellentExcellent Foam Density (g/mL) 0.200 0.197 0.140 0.175 Collapse time at36° C. (sec) 175 >180 >180 >180

In one or more embodiments, there is provided a foamable formulationcomprising Petrolatum, and a fatty alcohol with optionally shea butter,wherein the formulation generates quality breakable foam. In one or moreembodiments, there is provided a foamable formulation comprisingPetrolatum, optionally a liquid oil, and a fatty alcohol with optionallyshea butter, wherein the formulation generates quality breakable foam.

Example 10 Oleaginous Compositions Containing Waxes

The influence of waxes on the foaming properties of oleaginousformulations was examined. The wax studied is Paraffin 51-53, which is aparaffin wax a mixture of solid saturated hydrocarbons having a meltingpoint between 51° C. and 53° C. As observed in Table 10 below,formulations C001 and C002 respectively containing 10% stearyl alcoholand up to 2.5% Paraffin 51-53 did not give rise to high quality foamsbut merely generated fairly good quality foam that quickly collapsed.Surprisingly, formulations C003 to C007, containing 5% or more Paraffin51-53 alone or in combination with stearyl alcohol generated qualityfoams that did not quickly collapse at 36° C. Increasing the amount ofwax resulted in improved collapse times. Unexpectedly, paraffin 51-53was able to produce a high quality foam with a collapse time in excessof 3 minutes in the absence of a fatty alcohol. Thus, in one or moreembodiments the foamer complex can be a paraffin wax alone or incombination with a foam adjuvant. Moreover, formulation C007 is anexample of a surfactant free, hydroxyl free, acid free, water freeformulation essentially free of polyols and alcohols.

Therefore, it has been discovered that quality oleaginous foams can beproduced without surfactant and even without fatty alcohols, where thefoaming agent is a wax such as Paraffin 51-53.

Manufacturing Procedure: Heavy mineral oil is heated to 60-70° C., waxesand fatty alcohols if present are added under mixing until completemelting. The formulation is cooled down to room temperature, packagingin canisters which are crimped with a valve, pressurized with propellantand equipped with an actuator.

TABLE 10 Oleaginous compositions containing waxes Formulations C001 C002C003 C004 C005 C006 C007 Heavy Mineral oil 89.00 87.50 85.00 89.00 87.5085.00 85.00 Stearyl alcohol 10.00 10.00 10.00 1.00 2.50 5.00 — Paraffin51-53 1.00 2.50 5.00 10.00 10.00 10.00 15.00 Total 100 100 100 100 100100 100 Propellant AP-70 8.00 8.00 8.00 8.00 8.00 8.00 8.00 Results FoamQuality Fairly Fairly Good Excellent Excellent Excellent Excellent GoodGood Collapse Time — — 95 >180 >180 >180 >180

Example 11 Comparative Example

Two foam formulations of the present disclosure (Formulations 012 and019) were compared with a foam formulation from patent U.S. Pat. No.3,419,658, Example 4 which contains high viscosity mineral oil, cetylalcohol, stearyl alcohol and isobutane. All the foam samples were testedfor bubble size. As described in Table 11a, the results from Example 4of U.S. Pat. No. 3,419,658, show a very large bubble size of 420micrometers which indicates a poor foam quality. It is known in the artthat large foam bubbles are prone to coalescence and lead to a poor foamstability. Moreover, application onto the skin is made difficult, sincethe foam sample from the prior art rapidly turned into a poorly absorbedrunny liquid upon rubbing. Therefore, the combination and concentrationof fatty alcohols described in the prior art fails to create qualityfoams suitable for topical application.

On the other hand, the formulations of the present disclosure provide avery small mean bubble size (74 micrometers for formulation 012 and 79micrometers for formulation 019), which indicates a good foam qualityand an extended physical stability. Foams with small bubble size alsohave improved organoleptic properties, which is of importance in orderto ensure a better patient compliance and a better skin feeling. Thesefoam formulations provide an easy application onto the skin, good skinabsorption and do not turn into runny liquids upon rubbing. It has thusbeen discovered that the combination of fatty alcohol, with fatty acidsand/or waxes has a clear advantages over the prior art and provides foamof improved quality, usability and stability.

TABLE 11a Comparative example Sample according to U.S. FormulationFormulation 3,419,658, 012 019 Example 4 Ingredient % w/w % w/w % w/wHeavy mineral oil 60.00 59.50 79.00 Light mineral oil 25.00 25.00 —Cyclomethicone 5.00 5.00 — Cetyl alcohol — — 3.00 Stearyl alcohol 5.001.50 3.00 Behenyl alcohol — 1.00 — Cetostearyl alcohol — 2.50 — Stearicacid 5.00 2.00 — Hydrogenated castor oil — 1.50 — Beeswax — 2.00 —Propellant Isobutane — — 15.00 Total 100.00 100.00 100.00 Propellant A4612.00 12.00 — Results Bubble Size (micrometers) 74 79 420 Ease ofapplication on skin Good Good Poor Skin Feeling Good Good Poor

Two foam formulations of the present disclosure (Formulations 012 and019) were also compared with placebo samples of formulations fromExample 3 and Example 4 of U.S. Pat. No. 6,140,355, which contains highviscosity mineral oil, cetostearyl alcohol and hydrocarbon propellants.As noted in Tabic 11b, placebo samples from Example 3 and Example 4 ofU.S. Pat. No. 6,140,355, are merely delivered as a bubbly liquids thatcollapse on release showing that the combination of fatty alcoholsdescribed in the prior art fails to create quality foams suitable fortopical application.

On the other hand, the formulation of the present disclosure provides afoam of good quality with an extended physical stability. It has thusbeen discovered that the combination of fatty alcohol with fatty acidsand/or waxes has a clear advantage over the prior art and provides foamof improved quality and stability.

TABLE 11b Comparative example Placebo of Placebo of a sample a sampleaccording to according to Formulation U.S. 6,140,355, U.S. 6,140,355,012 Example 3 Example 4 Ingredient % w/w % w/w % w/w Heavy mineral oil60.00 96.00 96.00 Light mineral oil 25.00 — — Cyclomethicone 5.00 — —Stearyl alcohol 5.00 — — Cetostearyl alcohol — 4.00 4.00 Stearic acid5.00 — — Total 100.00 100.00 100.00 Propellant A46 12.00 — — Mixture ofn-butatne/ — 3.75 80.00 propane/isobutane 55:25:20 (Purifair ® 3.2)Results Foam Quality Good Poor Poor Collapse Time >180 0 0

Section B—Compositions with Tetracyclines Example 12 MinocyclineOleaginous Formulations with Different Hydrophobic Solvents

Minocycline foam formulations were prepared containing soybean oil,octyldodecanol, Medium Chain Triglycerides (MCT) oil and coconut oil,which are other examples of hydrophobic solvents. Parameters such asfoam quality, collapse time and density were evaluated. As described inTable 12, foams of good quality which did not collapse at 36° C. wereobtained in different compositions containing these hydrophobicsolvents. Coconut oil, which on its own is a semi solid paste like oil,was used in combination with liquid soybean oil.

TABLE 12 Formulation containing different hydrophobic solventsFormulations 244B 244A 199 216 232A 235 238 (1%) (4%) 245 248 251 252Heavy mineral oil 55.89 58.82 — — 58.14 — — — — — — Light Mineral oil25.00 25.00 25.00  — 25.00 4.44 1.44 4.44 3.04 4.44 5.54 Cyclomethicone5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 MCT oil — — —48.89 — — — — — — — Octyldodecanol — — — 12.00 — — — — — — — Coconut oil— — 25.00  — — 23.60 23.60 23.60 25.00 21.60 25.00 PPG 15 stearyl ether— — — 15.00 — — — — — — — Soybean oil — — 28.39  — — 50.00 50.00 50.0050.00 50.00 50.00 Lanolin — — — — — — — — — 2.0 2.00 Hydrogenated castor— 1.50 2.00 2.00 1.50 2.00 2.00 2.00 2.00 2.00 2.00 oil Beeswax 1.872.50 2.50 2.00 2.00 2.00 2.00 2.00 2.00 2.00 Cholesterol — — — — — — — —2.50 — — Myristyl alcohol 3.00 — — — — 2.50 2.50 2.50 — 2.50 —Cetostearyl alcohol — 2.50 — 2.50 2.50 3.50 3.50 1.50 1.50 3.50 2.50Stearyl alcohol 5.00 1.50 5.00 5.00 1.50 1.50 1.50 3.50 3.50 1.50 1.50Behenyl alcohol — 0.70 1.00 1.00 1.00 1.10 1.10 1.10 1.10 1.10 1.10Aerosil (SiO2) — — — — 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Stearic acid5.00 2.00 5.00 5.00 2.00 3.00 3.00 3.00 3.00 3.00 2.00 Minocycline HCl1.11 1.11 1.11 1.11 1.11 1.11 4.11 1.11 1.11 1.11 1.11 Total 100 100100    100 100 100 100 100 100 100 100 Propellant A46 — 12.00 — 12.00 —12.00 12.00 12.00 12.00 12.00 12.00 Propellant A70 8.00 — 8.00 — 8.00 —— — — — — Results Foam Quality G E E G E E G E E G G Collapse Timeat >180 160 >180     150 >180 >180 110 140 >180 >180 >180 36° C. (sec)Foam Density (g/mL) 0.082 0.225  0.149 0.293 0.237 0.284 0.193 0.2950.211 0.223 0.167

Comments: All the foams were of high, quality and had a collapse time at36° C. in excess of 100 seconds, a foam density of less than 0.3 g/mland the formulations were able to withstand 4 Freeze and Thaw Cycles(FTC) and still generate foam of high quality with a collapse time at36° C. in excess of 100 seconds. The pre-foam-formulation in the aboveformulations, before the addition of propellant, are semi-solid gel-likehomogeneous compositions where no separation or sedimentation of theingredients is observed.

Example 13 Stability of a Tetracycline Antibiotic in OleaginousFormulations

Tetracycline antibiotics are known to be very unstable active agentsthat are degraded by a wide range of commonly used pharmaceuticalexcipients. For example, it has been found that minocycline is degradedin a few days by different hydrophilic solvents (such as water,glycerin, sodium PCA, propylene glycol and polyethylene glycols), bywater dispersed polymers (such, as xanthan gum, poloxamers, carbomers,methocel, sodium CMC) and by surfactants (such as polysorbates, sorbitanesters, polyoxyalkyl esters and also lanolin-based surfactants). Thus,the achievement of a long term stable foamable formulation oftetracycline antibiotics described herein, was a major challenge andrequired both extensive research and creativity.

The following example illustrates the physical stability of foams andthe chemical stability of minocycline HCl (“MCH”) in oleaginousformulations, namely 238, 244B and 252 as described in Tables 13a,13b(i), 13b(ii) and 1.3c below. In an accelerated stability study,samples were stored at 40° C., and the concentrations of minocycline HClwere determined by UPLC. The stability test results following 2 months,3 months and 6 months of storage are shown in Tables 13b(i) and 13b(ii).

TABLE 13a Composition of foam formulation incubated at 40° C.Formulations 238 244B 252 Ingredients % w/w % w/w % w/w Heavy mineraloil 58.14 — — Light mineral oil 25.00 4.44 5.54 Cyclomethicone 5.00 5.005.00 Coconut oil — 23.60 25.00 Soybean oil — 50.00 50.00 Lanolin — —2.00 Hydrogenated castor oil 1.50 2.00 2.00 Beeswax 2.00 2.00 2.00Cetostearyl alcohol 2.50 3.50 2.50 Stearyl alcohol 1.50 1.50 1.50Behenyl alcohol 1.00 1.10 1.10 Myristyl alcohol — 2.50 — Aerosil (SiO2)0.25 0.25 0.25 Stearic acid 2.00 3.00 2.00 Minocycline HCl 1.11 1.111.11 Total 100.00 100.00 100.00 Propellant A46 — 12.00 12.00 PropellantAP-70 8.00 — — Results Foam quality Excellent Excellent ExcellentCollapse Time (sec) >180 >180 >180 Foam density (g/mL) 0.237 0.284 0.167

TABLE 13b(i) Chemical Stability results of foam compositions containingminocycline HCl Minocycline content (% of label claim) after 2 after 3after 6 months at months at months at Formulation T0 40° C. 40° C. 40°C. 238 98.6 95.7 96.0 92.9 244B 98.7 97.1 93.8 90.3 252 99.0 96.5 102.3NM NM = not measured

TABLE 13b(ii) Physical Stability results of foam compositions containingminocycline HCl after 2 after 3 after 6 For- months months monthsmulation Test at T0 at 40° C. at 40° C. at 40° C. 238 Foam QualityExcellent Good Good Good Collapse Time (sec) >180 >180 160 NM FoamDensity 0.237 0.259 0.289 0.263 (g/mL) 244B Foam Quality Excellent GoodGood Good Collapse Time (sec) >180 >180 >180 NM Foam Density 0.284 0.256NM 0.232 (g/mL) 252 Foam Quality Good Fairly Fairly NM Good GoodCollapse Time (sec) 150 150 NM NM Foam Density 0.167 0.126 0.142 NM(g/mL) NM = not measured

Very surprisingly, and despite the known instability of tetracyclineantibiotics, the accelerated stability results of formulations 238 and244B after 2 months, 3 months and 6 months at 40° C. showed minimaldegradation of the active agent in the formulations. The formulationsdisclosed herein thus show an extended accelerated stability for thetetracycline antibiotic active agent and an outstanding physicalstability.

Regarding formulation 252, the Table indicates that foam qualitydecreases with time under accelerated stability storage at 40° C.Without being bound to any theory, and by comparing the ingredientspresent in formulations 244B and 252 and results with otherformulations, it may be assumed that the decrease in foam quality islikely due to the presence of significant amounts of lanolin which mayhave some form of incompatibility with one or more components of theformulation. So in certain embodiments the formulations may beessentially free of lanolin, for example, where long term physicalstability is required. It may be, however, that in certain otherembodiments lanolin can be successfully included either in loweramounts, or by combination of lanolin with additional ingredients (suchas surfactants, polymers, etc) and the formula can be physically stablein the short, medium or long term.

These results further illustrate the difficulty, complexity andunexpected and non obvious achievement of discovering surfactant freeand water free formulations containing sensitive active agents that arechemically stable and are also physically stable over short term, mediumterm and/or long term periods. Testing and identifying single substancesthat are compatible chemically with the active agent is not sufficient.Combining multiple substances, which on their own are compatible canlead to collective incompatibility The discovery and knowledge ofsubstances are chemically compatible does not presume physical stabilityof the composition or vice-versa. Running a compatibility study betweenindividual formulation components and the active agents does not ensurenor achieve physical stability. Discovering combinations of ingredientsthat can lead to a physically stable formulation in the absence ofsurfactant, is itself unexpected. Further, adding propellant candestabilize the formulation as can expelling the formulation from apressurized canister and ultimately achieving a quality foam that isstable but breakable on application of modest shear force is far fromstraightforward.

It has further been discovered that the propellant has a positiveinfluence on the homogeneity of the formulation. After 2 months ofstorage at 40° C., several aliquots of foam formulations 238 as well aspre-foam formulation (liquid preparation without the addition of thepropellant) were tested for minocycline content in order to determine towhat extent the active agent is homogeneously dispersed. In the pre-foamformulation, high differences were found in the minocycline content,showing that the active agent is not homogeneously dispersed.Surprisingly, the foam formulations containing propellant demonstrated,an increase in the minocycline content homogeneity, which is of highimportance in pharmaceutical applications in order to ensure areproducible and accurate dose delivery. Without being bound to anytheory, it can be assumed that inter alia the propellant acts as asolvent to the hydrophobic carrier and also as a dispersing agent, byreducing the formulation viscosity within the canister.

In another experiment, a PFF sample of formulation 244 1% was storedduring 6 months at 40° C. and tested for API content uniformity. It wasfound that minocycline was homogeneously dispersed into thepre-foam-formulation even after prolonged incubation at 40° C. In one ormore embodiments, there is provided a formulation wherein the activeingredient is homogeneously dispersed in the pre-foam-formulation andremains homogeneously dispersed after 2, 3 and/or 6 months of incubationat 40° C.

An ex-vivo study of the skin stability of a minocycline oleaginous foamformulation according to the present disclosure was performed incomparison with a reference minocycline gel, which comprised, amongstother components, water, ethanol, and propylene glycol. Gel and foamsamples were applied on pig ear skins, incubated for 6 hours at 35° C.and the skin concentrations of minocycline HCl and its 4-epi degradantwere determined by liquid chromatography.

As shown in Table 13c below, a rapid degradation of minocycline wasobserved after 6 h on skin treated with the reference silicone basedgel. The minocycline content decreased by 34% and its 4-epi degradantcontent reached 19.4% showing that the gel reference product fails todeliver the all the antibiotic amount to the skin in its active form.

In the case of the foam formulation, very surprisingly, and despite theknown instability of minocycline, the skin stability results after 6 hshowed a very minimal degradation of the active agent: with the contentof 4-epi degradant only reached 3.3% and no detectable decrease wasobserved in the amount of minocycline. Therefore, the foam formulationhas an active protective effect on the tetracycline antibiotic uponcontact with the skin, and prevents its degradation on the target siteof treatment over several hours.

TABLE 13c Skins stability results of foam and gel compositionscontaining minocycline HCl Reference Oleaginous Silicone Foam GelFormulation Initial minocycline skin concentration 96.90 92.20 Initial4-epi degradant skin concentration 2.60 0.80 Minocycline skinconcentration 64.00 93.70 after 6 h at 35° C. 4-epi degradant skinconcentration 19.40 3.30 after 6 h at 35° C.

Example 14 Optimization of Minocycline Oleaginous Formulations

Part A—Wax Effect on Formulation Homogeneity

Formulations were prepared, containing various concentrations of waxesand checked for their pre-formulation homogeneity, as described in Table14a.

TABLE 14a Influence of waxes on formulation homogeneity Formulation 244282 283 287 288 276 Ingredients % w/w % w/w % w/w % w/w % w/w % w/wLight Mineral oil 4.44 5.04 5.04 4.04 2.04 4.44 Cyclomethicone 5 5 5 5 55 Coconut oil 23.6 25 25 25 25 23.6 Soybean 50 50 50 50 50 50Hydrogenated castor oil 2 — 2 1 2 — Beeswax 2 2 — 2 3 — Paraffin 51-53 —— — — 6.5 Myristyl alcohol 2.5 2.5 2.5 2.5 2.5 — Cetostearyl alcohol 3.53.5 3.5 3.5 3.5 3.5 Stearyl alcohol 1.5 1.5 1.5 1.5 1.5 1.5 Behenylalcohol 1.1 1.1 1.1 1.1 1.1 1.1 Aerosil (SiO2) 0.25 0.25 0.25 0.25 0.250.25 Stearic acid 3 3 3 3 3 3 Minocycline HCl 1.11 1.11 1.11 1.11 1.111.11 Total 100.0 100.0 100.0 100.0 100.0 100.0 AP-70 12.0 12.0 12.0 12.012.0 10.0 Results PFF separation with MCH No No No Yes Yes No PFFseparation placebo No Yes No N/A N/A Yes Ratio Fatty alcohol to fatty2.86:1 2.86:1 2.86:1 2.86:1 2.86:1   2:1 acid Ratio Fatty alcohol plus 2.9:1  5.8:1  5.8:1 3.86:1 2.32:1 1.4:1 fatty acid to wax (total) FoamQuality Good Good Good Good N/A Good (slight collapse)

It was observed that in the presence of hydrogenated castor oil, no tominor PFF separation was observed (see formulation 244 with beeswax andformulation 283 without beeswax). It was also observed that removal ofhydrogenated castor oil resulted in PFF separation in placeboformulation, but the PFF surprisingly regained its homogeneity uponaddition of minocycline (see formulation 282). It was observed that anincrease in beeswax concentration resulted PFF separation (seeformulation 288), and that a decrease in hydrogenated castor oilconcentration resulted in PFF separation (see formulation 287). Ingeneral, it appears that stability in the above formulations is a morecomplex issue than simply being a function of the acid/alcohol to waxratio and that whilst no separation was seen at the higher ratio offatty alcohols and acids to waxes of about 6:1 and also at the lowerratio of about 7:5 some separation was seen in some inbetween ratios.Moreover the effect seems unrelated to the fatty alcohol:fatty-acidratio which is constant with one exception.

It was observed that in the presence of Paraffin wax 51-53, PFFseparation occurred in placebo formulation but the PFF regained itshomogeneity upon addition of minocycline (see formulation MCH276). Thehomogeneity of the placebo formulation may be improved by the use ofhigher concentrations of paraffin wax or by the combination with anotherwax such as beeswax or hydrogenated castor oil. In one or moreembodiments hydrogenated caster oil is used to prevent separation or torestore homogeneity. In one or more embodiments a tetracycline is usedto prevent separation or to restore homogeneity. In one or moreembodiments a paraffin wax is used to prevent separation or to restorehomogeneity.

Part B—Propellant Effect

Formulation 244 was prepared, containing various types andconcentrations of propellant and checked for foam properties, asdescribed in Table 14b.

TABLE 14b Influence of propellant on foam properties of formulationMCH244 Propellant Propellant Foam Quality type % w/w Upright canisterInverted canister Shakability AP-70 8 Good Good with 2 minor collapse 10Good Good 2 12 Good Good 2 14 Good Good 2 16 Good Good 2 A-46 8 Goodwith Good with 2 minor collapse minor collapse 10 Good N/A 2 12 GoodGood with 2 minor collapse 16 Good with Good with 2 minor collapse minorcollapse Tetrafluoro- 8 Excellent Excellent 1 ethane 12 ExcellentExcellent 2 (Dymel 134a) 16 Excellent (stiff) Excellent (stiff) 2

It was observed that replacing AP-46 with propellant AP-70 resulted inimproved foam quality. Furthermore, the use of higher concentrations ofAP-70 also improved foam quality. It was noticed that the use ofTetrafluoroethane also improved foam quality but however slightlyreduced shakability. Higher levels of propellant resulted in a stiffnessbeing observed in the foam.

Part C—Fatty Alcohol to Fatty Acid Ratio Effect

Formulations were prepared, containing various fatty alcohol to fattyacid ratios and a constant level of wax and were checked for theirfoaming properties and pre-foam formulation homogeneity, as described inTable 14c.

TABLE 14c Influence of fatty alcohol to fatty acid ratio on foamproperties and formulation homogeneity Formulations MCH244 MCH289 MCH277MCH280 Ingredients % w/w % w/w % w/w % w/w Light Mineral Oil 4.44 3.444.44 4.44 Cyclomethicone 5 5 5 5 Coconut Oil 23.6 23.6 23.6 23.6 Soybean50 50 50 50 Hydrogenated 2 2 2 2 Castor Oil Beeswax 2 2 2 2 MyristylAlcohol 2.5 2.5 2.5 2.5 Cetostearyl Alcohol 3.5 3.5 3.5 3.5 StearylAlcohol 1.5 2.5 3 4.5 Stearic Acid 3 3 1.5 — Behenyl Alcohol 1.1 1.1 1.11.1 Aerosil (Silicon dioxide) 0.25 0.25 0.25 0.25 Minocycline HCl 1.111.11 1.11 1.11 Total 100 100 100 100 Propellant AP-70 12 12 12 12Results PFF separation with HCl No N/A No No PFF separation placebo NoN/A No No Shakability 2 2 2 1 Foam quality Good Good Good Good (stiff)(slightly (close to collapses) Fairly Good) Ratio Fatty alcohol 0.5:10.83:1 1:0.5 ∞ to fatty acid Ratio Fatty alcohol plus 2.9:1 3.15:1 2.9:12.9:1 fatty acid to wax (total)

All the foams were of quality the foam quality appears slightly improvedas the ratio of fatty alcohol to acid decreased. Lowest shakabilityresults were seen when the fatty acid was omitted. None of theformulations displayed separation and they were all homogenous. Moreoverthe effect seems unrelated to the fatty alcohol:fatty acid ratio whichis constant with one exception.

Example 15 Skin Penetration and Skin Residence Studies

Part A—Skin Penetration

As can be seen from the results in Table 15A below, minocycline isdelivered intradermally at sufficient levels to treat skin infectionsbut does not pass through the skin transdermally and therefore topicalapplication should be free from adverse systemic effects.

TABLE 15A In Vitro Skin Delivery: formulation 244 with 1% and 4%minocycline μg Minocycline (Mean) 244 foam 1% (n = 5) 244 foam 4% (n =6) Stratum Corneum 1 11.45 46.91 Stratum Corneum 2 1.62 12.43 TotalStratum Corneum 13.07 59.34 Viable Skin 1.03 2.68 Total IntradermalDelivery 14.10 62.02 Receiving Compartment 0.00 0.00

The following conclusions can be drawn:

-   1. Transdermal delivery: Following 24 hours of exposure, the amount    which was found in the receptor cells was below the limit of    quantification (LOQ) of the analytical method (LOQ=2 μg/mL).-   2. Intra-dermal delivery (delivery into the skin): The total mean    amount of Minocycline in the skin following 24 hours of exposure was    14 μg for the 1% formulation and 62 μg for the 4% formulation. The    weight of skin at the delivery area is about 100 mg, which implies    that the concentration of Minocycline in the skin following 24 hours    of exposure is about 140 μg/gr of skin for the 1% formulation and    about 620 μg/gr for the 4% formulation. According to the literature,    the minimum inhibitory concentration (MIC) for Minocycline is less    than 4 μg/mL, and therefore, it can be concluded that the    concentrations found in the skin are sufficient to treat bacterial    skin infections.    Part B—Skin Residence

The objective of this study is to assess the degradation of Minocyclinefollowing exposure to skin. Formulation MCH232A, containing 1%Minocycline was applied to freshly retrieved pig's ear skin and sampleswere analyzed during 6 hours of exposure. As presented in Table 15B, theproduct remained stable during the exposure and only minor amountsconverted into the 4-epi degradation product.

TABLE 15B Skin Residence Time T0 1 Hour 3 Hours 6 Hours Substance MCH4-Epi MCH 4-Epi MCH 4-Epi MCH 4-Epi % of Applied Dose 92.20% 0.8% 96.9%1.20% 87.8% 2.40% 93.7% 3.20%

Example 16 Microbial Properties of Oleaginous Minocycline Compositions

Part A—Microbial Load

Formulation 2.52 was examined for microbial load following 3 monthsstorage at 25° C., as a representative formulation. As shown in Table16A, the test revealed an absence of microorganisms in the formulation.

TABLE 16A Microbial Count and Detection of Specific Microorganisms inFormulation MCH252 Following Storage for 3 Months at 25° C. Totalaerobic Total combined Staphylococcus microbial yeast & mold E. coli,Pseudomonas Salmonella, aureus, presence Formulation count (cfu/g) count(cfu/g) presence aureus, presence presence (coagulase test) Sample 1 <10<10 negative negative negative negative Sample 2 <10 <10 negativenegative negative negativePart B—Antimicrobial Effectiveness

As seen in Table 16B, results for formulation 238, as a representativeexample, were found to be in agreement with USP acceptance criteria forincubation times at 2 weeks. The number of colonies counted in samplesfollowing incubation period of 2 weeks (14 days) was found below 10cfu/g, indicating approximately a 5-log reduction from the initialmicrobial inoculated level for E. coli, S. aureus, and P. aeruginosa.After an incubation period of 14 days, a 2-log reduction from theinitial challenge level was found with C. albicans and less than a 1-logreduction was found with A. niger.

TABLE 16B Antimicrobial effectiveness in non aqueous Formulation 238Initial Before challenge No. of surviving microorganisms, inoculation,level, cfu/g Test organisms cfu/g cfu/g 1 day 1 week 2 weeks E. coli <106.1 × 10⁵ <10 <10 <10 Staphylococcus aureus <10 4.3 × 10⁵ <10 <10 <10Pseudomonas aeruginosa <10 2.8 × 10⁵ <10 <10 <10 Candida albicans <102.1 × 10⁵ 7.5 × 10⁴ 4.7 × 10⁴ 3.6 × 10³ Aspergillus niger <10 5.9 × 10⁵3.4 × 10⁴ 7.5 × 10⁴ 2.3 × 10⁵ Unininoculated control — <10 <10 <10formulation 232A

It should be noted that antimicrobial effectiveness herein waschallenged in non aqueous media.

Part C—In-Vitro Effect of 244 1% on Microbial Growth

An in-vitro study showed that formulation 244 with 1% minocyclineinhibited the growth of Streptococcus pyogenes, Pseudomonas aeruginosa,Staphylococcus aureus, as well as a methicillin-resistant strain ofStaphylococcus aureus (MRSA) and Propionbacterium acnes, as shown inTable 16C.

TABLE 16C In Vitro Antibacterial Effect: Comparison between 10 μl of 2442%, Fucidin Ointment 2% and Placebo-Diameter of inhibition (mm). 244 244Placebo Fucidin 1% Inhibition Inhibition Inhibition Diameter DiameterDiameter Staphylococcus aureus 6538 >40, >40, >40 mm 13, 21, 20mm >40, >40, >40 mm Pseudomonas aeruginosa 9027 40, 40, 40 mm 0, 0, 0 mm11, 12, 16 mm Staphylococcus aureus MRSA 43300 >40, >40, >40 mm 17, 18,20 mm 40, 40, 38 mm Streptococcus pyogenes 19615 38, 43, 40 mm 12, 15,11 mm 10, 12, 22 mm Propionbacterium acnes 32, 30, 35 mm NA NA 0 =Ineffective; >30 = Very EffectivePart D—Water Activity (Aw)

The water activity measured on formulation 232A was 0.47, which preventsthe growth of bacteria, fungi and yeast. Based on this information andabove test results, it appears that the waterless surfactant freeformulations herein will not support bacterial growth.

Example 17 Eye Irritation Study—HET CAM

The potential of compounds to cause irreversible or severe eyeirritation or corrosion may be detected by observing adverse changes,which occur in the chorioallantoic membrane (CAM) of the egg afterexposure to test chemicals. Fertilized hen's eggs are rotated in anincubator for 9 days, after which any defective eggs are discarded. Theshell around the air cell is removed and the inner membranes areextracted to reveal the chorionallantoic membrane. Test chemicals areadded to the membrane and left in contact for up to 5 minutes. Themembrane is examined for vascular damage and the time taken for injuryto occur is recorded. Irritancy is scored according to the speed atwhich damage occurs. To validate the HET-CAM data, Positive & NegativeControls and Vehicle Control (if applicable), are tested in parallel tothe Test Item. For each Test Item, Positive and Negative Controls, meanscores of replicate eggs is determined. Irritation Score (IS) isinterpreted as follows:

Irritation Score Irritation Classification 0-0.9 Non-Irritant 1-4.9Slight Irritant 5-8.9 Moderate Irritant 9-21 Severe Irritant

As can be seen in Table 17 using the in vitro irritation HET-CAM,formulations 244 placebo, with 1% minocycline hydrochloride and with 4%minocycline hydrochloride, demonstrated no signs of irritation.

TABLE 17 Eye irritation HET CAM studies Irritation Treatment ScoreClassification Negative Control (Saline 0.9%) 0 Non irritant PositiveControl (NaOH 4 mg/ml) 17.09 Severe 244-1% MCH 0 Non irritant 244-4% MCH0 Non irritant 244-Placebo 0 Non irritant

Example 18 Anti-Inflammatory Effects of Oleaginous MinocyclineCompositions

UVB irradiation of the skin is known to decrease cell viability, totalantioxidant capacity, while increasing the levels of inflammation(pro-inflammatory cytokines secretion) and epidermal cell apoptosis.

Pre-Treatment with Formulation 244

Specimens of human skin in organ culture were treated topically withformulation_244 for 24 hours, then irradiated with UVB (400 mJ/cm2) andincubated for additional 72 hours. Apoptosis activation was measured 24h post-irradiation by measuring the extent of caspase 3 activity inepidermal sheets.

Table 18a and Table 18b demonstrate the effect of formulation 244 with1% and 4% minocycline on epidermal cell apoptosis and viabilityfollowing UVB irradiation of the skin organ culture. As shown in Table18a, apoptosis activation was significantly decreased by formulation 244in a dose-dependant manner. Cell viability, as measured by the MTT assay72 hours after irradiation was increased, as shown in Table 18b. One setof mediators implicated in apoptosis belong to the asparate-specificcysteinyl proteases or caspases. A member of this family, caspase-3 hasbeen identified as being a key mediator of apoptosis of mammalian cells.

TABLE 18a Effect of Formulation 244 on apoptosis activation in skinorgan culture after UVB irradiation Caspase 3 activity (slope/min)Non-irradiated Irradiated Carrier 24 177 244-1% MCH 4 100 244-4% MCH 369

TABLE 18b Effect of Formulation 244 on skin organ culture viabilityViability (RFU 540/590 nm) Non-irradiated Irradiated Carrier 6971.256207.5 244-1% MCH 7615.25 8862.25 244-4% MCH 8155.5 9015.5

Comments: It was observed that in the case of cells in contact with aplacebo formulation, irradiation causes a decrease in cell viability. Onthe other hand, in cells in contact with a formulation containingminocycline, higher cell viability was observed both before and afterirradiation compared to the placebo, which is a sign of cellregeneration. Therefore, the present formulation comprising minocyclineis able to prevent cell death in the case of irradiation and can evenstimulate or cause cell regeneration.

Treatment with Formulation 244 After UV Damage Induction

Specimens of human skin in organ culture were irradiated with UVB (400mJ/cm2) and incubated for additional 72 hours. Formulation 244 4% wasthen applied to the skin and apoptosis activation was measured 24 hpost-treatment by measuring the extent of caspase 3 activity inepidermal sheets.

As shown in Table 18c, Formulation 244 4% treatment resulted in about60% decrease in epidermal cell apoptosis.

TABLE 18c Therapeutic effect of Formulation 244 (application postirradiation) Caspase 3 activity (slope/min) Control 118 244-4% MCH 46

These results demonstrate that formulation 244 containing minocyclinehas protective and/or therapeutic properties in the case of UVB-inducedskin damage. It may therefore be able to reduce skin photo damage andphotoaging, and more generally to reduce oxidative stress andInflammation in skin pathologies which are known to be accompanied byapoptotic cell death.

Example 19 Compatibility Study

Procedure: Minocycline hydrochloride (“MCH”) was incubated as asuspension with various excipients at 25° C. and 40° C. for maximum ofsixty days or to the point where degradation was suspected. The ratiobetween MCH and the tested excipient is detailed below. Visualinspection was the major criterion for indication of compatibility. Thecolor of intact MCH suspension is pale yellow; and any change of color(e.g., to dark orange, red, green, brown and black) indicates oxidationor degradation.

Hydrophilic solvents were tested for compatibility with MCH at a ratioof MCH:excipient of 1:250. Dimethyl Isosorbide, Glycerin, Ethanol,Propylene glycol, Butylene Glycol, PEG 200, Hexylene Glycol, PEG 400,Dimethyl Sulfoxide and Diethylene glycol monoethyl ether were found tobe incompatible with MCH.

Oily emollients and waxes were tested for compatibility with MCH at aratio of MCH:excipient of 1:250 for Oily emollients and 1:50 for waxes.Hydrogenated castor oil, Castor oil, Cocoglycerides, Disopropyl adipate,Mineral oil light, Coconut oil, Beeswax, MCT oil, Cyclomethicone,Isododecane, Cetearyl octanoate, Gelled mineral oil, Isopropylmyristate, PPG 15 stearyl ether, Mineral oil heavy, Octyl dodecanol,White Petrolatum, Petrolatum (Sofmetic), Paraffin 51-53, Paraffin 51-53,Paraffin 58-62, Calendula oil, Shea butter, Grape seed oil, Almond oil,Jojoba oil, Avocado oil, Peanut oil, Wheat germ oil and Hard Fat werefound to be compatible with MCH. Pomegranate seed oil was found to beincompatible with MCH.

The compatibility of MCH with hydrophobic surfactant was testedfollowing solubilization of the surfactant in mineral oil (mineral oilwas previously shown to be compatible with MCH). Surfactants were testedfor compatibility with MCH at a ratio of MCH:excipient of 1:50. PEG 150distearate, Laureth 4, PEG 40 hydrogenated castor oil, PEG 75 lanolin,Glucam P20 distearate, PEG100 stearate, Glyceryl monostearate, PEG 40stearate, Montanov S (Cocoyl Alcohol (and) C12-20 Alkyl Glucoside)),Alkyl lactate, Benton gel, SPAN 60, Sorbitan sesquistearate, SPAN 40,SPAN 80, Tween 20, Ceteth 2, Sucrose stearic acid esters D1813,Ceteareth 20, Steareth 2/Steareth 21, Methyl glucose sesquistearate,Oleth 20, PPG 20 methyl glucose ether, Tween 60 were found to beincompatible with MCH. Sucrose stearic acid esters D1803, Sucrosestearic acid esters D1807 and Sucrose stearic acid esters D1811 werefound to be compatible with MCH; however, not all of them dissolved inoil (e.g. 1811, 1813).

Foam adjuvants were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Isostearyl alcohol, Behenyl alcohol, Stearylalcohol, Cetyl alcohol, Oleyl alcohol, Myristyl alcohol, Cetostearylalcohol, Palmitic acid, Stearic acid and Oleic acid were found to becompatible with MCH. Isostearic acid was not compatible with MCH.

Additives were tested for compatibility with MCH at a ratio ofMCH:excipient of 1:50. Aerosil and Menthol were found to be compatiblewith MCH. Titanium dioxide and Ethocel were not compatible with MCH.

Additives were tested for compatibility with MCH. Minimal quantities ofwater (100 μL) were added to MCH, suspended in excipients that haddemonstrated compatibility to examine whether water can enhanceoxidation/degradation in the absence or presence of antioxidant. Inparallel, antioxidants were added to the MCH suspensions comprisingwater. Antioxidants were also added to excipients which were found to benon compatible with MCH. Addition of water caused prompt degradation ofMCH. Addition of the antioxidants alpha-tocopherol, BHA/BHT and propylgallate did not prevent MCH degradation. Compatible excipients becameincompatible in the presence of water. Addition of antioxidants did notalter this result.

Example 20 Color and Pigmentation Study

Part A—Color Change

Samples of formulations 238 and 216 with 1% minocycline were incubatedduring 3 months at 25° C., 30° C. and 40° C. Following this period thefoam product was actuated and the change in color was observed. Minimalto no change was observed following 3 months storage at all threetemperatures.

Part B—Pigmentation

A large amount of MCH 244 4% was actuated on human skin to observewhether any skin pigmentation occurs. Minimal to no skin pigmentationfollowing rubbing the foam onto the skin was noticed, when observedafter about 30 seconds.

Example 21 Oleaginous “Oil-Gel” Compositions Stability

Formulations 244A and 244B were prepared without the addition ofpropellant, packaged in a tube and tested for stability during 8 days.The tubes were opened each day and exposed to air and moisture to mimictypical patient use. On days 0, 3, 5, and 8 an aliquot was removed andanalyzed. Results are presented in Table 21 and demonstrate that MCH inthese formulations was stable when tube was exposed to air and moistureon a daily basis. On visual inspection no color change was observedduring the eight day period. The contents of the tube were also observedafter a month and no visual difference was noted. The formulationspresented as homogeneous oil-gels. These gels are semi-solid at rest andliquefy upon application of shear forces. The agents are uniformlydistributed throughout the carrier. Upon slight rubbing, bothformulations readily liquefy in order to ensure an easy application andan optimal spreading of the composition. So not only are theseformulations capable of generating a high quality foam that is stableand breakable on application of shear force but can also be used as agel or ointment and whether applied as a foam or a gel or ointment it iseasy to spread, readily absorbable, relatively non greasy and non-stickyand can be used for the treatment of a great number of diseases andsyndromes affecting skin, mucosal membranes, eye and body cavities.

TABLE 21 Batch/Sample MCH % 4-Epi MCH % name T = 0 3 d 5 d 8 d T = 0 3 d5 d 8 d MCH 244A 99.38 100.13 100.6 100.8 1.65 1.7 1.6 1.6 MCH 244B99.00 99.70 100.4 NM 1.5 1.6 1.6 NM NM = Not measured

Example 22 Oleaginous Eye Compositions

Minocycline oleaginous compositions suitable for ophthalmic use wereprepared using ingredients allowed in pharmaceutical eye formulationaccording to the FDA Inactive Ingredients Guide.

Manufacturing Procedure: Heat Petrolatum and light mineral oil to 50-60°C. and add Cetyl alcohol. Mix until complete melting. Cool down to35-40° C., add minocycline, mix until formulation homogeneity isobtained and cool down to room temperature.

TABLE 22 Ophtalmic oleaginous compositions containing minocyclineFormulations O-001 O-002 Ingredients % w/w % w/w White Petrolatum (hard)50.00 25.00 Light mineral oil 48.40 73.40 Cetyl alcohol 0.50 0.50Minocycime HCl 1.11 1.11 Total 100 100

Formulations O-001 and O-002 gave homogeneous oil-gels suitable for usein ophthalmic preparations. The two formulations differ in theirtexture, formulation O-002 being more liquid due to the inclusion ofhigh amounts of liquid oils. Upon slight rubbing, both formulationsreadily liquefy in order to ensure an easy application onto the eye andan optimal spreading of the composition. For application as a foam, awax or shea butter or a hydrogenation caster oil may be usefully addedtogether with a propellant. Shea butter can be obtained in severaldifferent formats: Liquid, semi solid or butter like consistency. In thepresence of another hydrophobic solvent good shakability of a foamableformulation with petrolatum can be obtained even with semi shea butterof solid or butter like consistency. In one or more embodiments, thefoamer complex can be a fatty alcohol and shea butter. In one or moreembodiments, the foamer complex can be a fatty acid and shea butter. Inone or more embodiments, the foamer complex can be a hydrogenated casteroil and shea butter. In one or more embodiments, the foamer complex canbe a wax, such as beeswax or paraffin wax and shea butter.

Section C—Compositions with Active Ingredients Example 23 OleaginousFormulations Containing Different Active Ingredients

Several active ingredients (API) were added to formulation 012 in orderto assess the compatibility between the oleaginous foam vehicle andvarious APIs. Parameters such as foam quality, and collapse time wereevaluated as described in Table 23a and 23b below.

TABLE 23a Oleaginous compositions containing different activeingredients 012A 012B 012C 012D 012E 012F 012G Ingredient % w/w % w/w %w/w % w/w % w/w % w/w % w/w Heavy mineral oil 60.00 60.00 60.00 60.0060.00 60.00 60.00 Light mineral oil 25.00 25.00 25.00 25.00 25.00 25.0025.00 Cyclomethicone 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Stearyl alcohol5.00 5.00 5.00 5.00 5.00 5.00 5.00 Stearic acid 5.00 5.00 5.00 5.00 5.005.00 5.00 Total 100 100 100 100 100 100 100 Doxycycline Hyelate 1.00 — —— — — — Betamethasone Valerate — 0.12 — — — — Progesterone — — 0.05 — —— Terbinafine — — — 1.00 — — — Metronidazole — — — — 1.00 — — Calcitriol— — — — — 0.05 — Naproxen — — — — — — 5.00 Propellant A46 12.00 12.0012.00 12.00 12.00 12.00 12.00 Results Foam Quality Good Good Good GoodGood Good Good Collapse Time (sec) >180 >180 >180 >180 >180 >180 >180

TABLE 23b Oleaginous compositions containing calcipotriol 012HIngredient % w/w Hard Fat (Softisan 378) 18.00 Hydrogenated castor oil2.00 Aluminum Starch Octenylsuccinate 1.00 Capric Caprylic Triglycerides20.00 Heavy mineral oil 39.99 Paraffin wax 58-62 10.00 Stearyl alcohol2.00 Cetyl alcohol 3.00 Cetostearyl alcohol 4.00 Calcipotriol 0.01 Total100.00 Propellant AP-70 8.00 Results Foam Quality Excellent CollapseTime (sec) >180

Formulations containing Doxycycline Hyclate, Betamethasone Valerate,Progesterone, Terbinafine, Metronidazole, Calcitriol, Calcipotriol andNaproxen gave rise to breakable foams of good quality which were stableat 36° C. during more than 3 minutes.

Example 24 Oleaginous Formulations Containing Calcitriol and StabilityExample 24A Surfactant Free Formulations

Foam formulations containing calcitriol as an active ingredient wereprepared. Parameters such as foam quality, collapse time and densitywere evaluated. As described in Table 24A, foams of good to excellentquality which did not collapse at 36° C. for at least more than twominutes were obtained in different compositions containing thesehydrophobic solvents.

Manufacturing procedure: Hydrophobic solvents are mixed together andheated to 70-80° C., fatty alcohols are added and mixed until completemelting. The mixture is cooled to 40-45° C. Calcitriol is added andmixed until dissolved and until a uniform preparation is obtained. Themixture is cooled to 15-20° C. using an ice bath while mixing. Thepreparation is filled into canisters which are crimped with a suitablevalve, pressurized with propellant and equipped with an actuator.

TABLE 24A Formulations without surfactant containing calcitriolFormulation C016 C017 C16B C16C Calcitriol 0.0015 0.0015 0.0015 0.0015Behenyl alcohol 1.00 1.00 1.00 1.00 Benzyl alcohol — 1.00 — — Butylatedhydroxytoluene 0.04 0.04 0.04 0.04 Capric/Caprylic triglycerides 5.95855.9585 5.9585 11.9585 Cetostearyl alcohol 4.00 4.00 4.00 4.00 Cetylalcohol 3.00 3.00 3.00 3.00 Heavy Mineral oil 50.00 40.00 50.00 47.00Light Mineral oil 25.00 25.00 — 23.00 Myristyl alcohol 2.00 2.00 2.002.00 Paraffin 51-53 6.00 6.00 6.00 5.50 Soybean oil — — 25.50 — Stearylalcohol 3.00 3.00 2.50 2.50 Water, purified — 9.00 — — Total 100 100 100100 Propellant AP-70 10.00 8.00 8.00 8.00 Results Foam Quality E E E ECollapse Time at 36° C. (sec) >180 >180 >180 155 Foam Density (g/mL)0.223 0.216 0.228 0.205

Example 24B Stability of a Vitamin D Derivative in OleaginousFormulations

The following example illustrates the physical and chemical stability offoams and the chemical stability of Calcitriol in an oleaginousformulation, namely C016 as described in Example 16A. In an acceleratedstability study, samples were stored at 40° C., and the concentration ofCalcitriol was determined by UPLC. The physical and chemical stabilitytest results following 4 weeks, 8 weeks and 12 weeks of storage areshown in Table 24b(i) and 24b(ii).

TABLE 24b(i) Chemical Stability results of foam composition C016containing Calcitriol after 4 weeks after 8 weeks after 12 weeks Test T0at 40° C. at 40° C. at 40° C. Calcitriol content 100.2 98.6 99.3 101.8(% of label claim)

TABLE 24b(ii) Physical Stability results of foam composition C016containing Calcitriol after after after 4 weeks 8 weeks 12 weeks Test T0at 40° C. at 40° C. at 40° C. Foam Quality Excellent Excellent ExcellentExcellent Collapse Time (sec) >180 >180 >180 >180

Example 25 Stability of a Corticosteroid in Oleaginous Formulations

The following example illustrates the physical and chemical stability offoams and the chemical stability of Mometasone Furoate in an oleaginousformulation M03 as described in Table 25(i). In an accelerated stabilitystudy, samples were stored at 40° C., and the concentration ofMometasone Furoate was determined by UPLC. The stability test resultsfollowing 4 weeks, 8 weeks and 12 weeks of storage are shown in Table25(ii) and 25(iii).

TABLE 25(i) Formulations without surfactant containing MometasoneFuroate Formulation M03 Light mineral oil 75.00 Heavy mineral oil 59.15Cyclomethicone 5.00 Behenyl alcohol 1.00 Cetostearyl alcohol 7.50Stearyl alcohol 1.50 Hydrogenated castor oil 1.50 Beeswax 2.00 Acrosil0.25 Stearic acid 2.00 Mometasone furoate 0.10 Total 100 PropellantAP-70 10.00 Results Foam Quality E Collapse Time at 36° C. (sec) >180Foam Density (g/mL) 0.181

TABLE 25(ii) Chemical Stability results of foam composition M03containing Mometasone Furoate after 4 weeks after 8 weeks after 12 weeksTest T0 at 40° C. at 40° C. at 40° C. Mometasone 101.0 97.9 93.5 94.6Furoate content (% of label claim)

TABLE 25(iii) Physical Stability results of foam composition M03containing Mometasone Furoate after after after 4 weeks 8 weeks 12 weeksTest T0 at 40° C. at 40° C. at 40° C. Foam Quality E,xcellent ExcellentExcellent Excellent Collapse Time (sec) >180 180 155 >180

What is claimed is:
 1. A method of treating rosacea, consisting ofadministering a surfactant free foam composition, obtained from afoamable composition dispensed from a container, to a subject in needthereof, wherein the foamable composition consists of: i) a carrierconsisting of: a) about 60% to about 95% by weight of the carrier of ahydrophobic solvent; b) about 0.1% to about 20% by weight of the carrierof at least one fatty alcohol, wherein the fatty alcohol has a carbonchain length of 14 to 22 carbons; c) about 0.1% to about 20% by weightof the carrier of at least one fatty acid, at least one wax, at leastone shea butter, or mixtures of two or more thereof, wherein the fattyacid has a carbon chain length of 12 to 28 carbons, and the wax isselected from the group consisting of a beeswax, a hydrogenated castoroil, a paraffin wax, a wax that is solid at room temperature, and amixture of any two or more thereof; and d) one active agent, wherein theone active agent is minocycline or a salt thereof; and ii) a liquefiedor compressed gas propellant; wherein the foamable composition comprises15% or less of petrolatum by weight of the carrier; wherein the foamablecomposition is essentially waterless; wherein the foamable compositionis free of polymeric agent; wherein, upon dispensing, the foamablecomposition forms a foam; and wherein the subject in need thereof hasrosacea.
 2. The method of claim 1, wherein the fatty alcohol is selectedfrom the group consisting of stearyl alcohol, cetyl alcohol, behenylalcohol, myristyl alcohol, and a mixture of any two or more thereof; andwherein the hydrophobic solvent is selected from the group consistingof: an avocado oil, a calendula oil, cocoglycerides, a coconut oil, acyclomethicone, a grape seed oil, a heavy mineral oil, a jojoba oil, alight mineral oil, medium chain triglyceride (MCT) oil, octyldodecanol,a peanut oil, a PPG-15 stearyl ether, a soybean oil, a wheat germ oil,and a mixture of any two or more thereof.
 3. The method of claim 1,wherein the hydrophobic solvent is selected from the group consisting ofan avocado oil, a calendula oil, cocoglycerides, a coconut oil, acyclomethicone, a grape seed oil, a heavy mineral oil, a jojoba oil, alight mineral oil, medium chain triglyceride (MCT) oil, octyldodecanol,a peanut oil, a PPG-15 stearyl ether, a soybean oil, a wheat germ oil,and a mixture of any two or more thereof.
 4. The method of claim 1,wherein the fatty acid comprises stearic acid.
 5. The method of claim 1,wherein the foamable composition comprises at least one fatty alcoholand at least one wax, or at least one fatty alcohol and at least onefatty acid, or at least one fatty alcohol, at least one fatty acid, andat least one wax.
 6. The method of claim 1, wherein the wax comprises acombination of a beeswax and a hydrogenated castor oil, wherein theratio of beeswax to hydrogenated castor oil is between about 1:1 andabout 5:1.
 7. The method of claim 1, wherein the ratio of fatty alcoholto wax is between about 4:1 and about 1:4.
 8. The method of claim 1,wherein the foamable composition is free of short chain alcohols.
 9. Themethod of claim 1, wherein the hydrophobic solvent is a liquid oil. 10.The method of claim 1, wherein the foamable composition comprises about10% or less of petrolatum by weight of the carrier.
 11. The method ofclaim 1, wherein the foamable composition comprises a fatty acid and afatty alcohol at a ratio of between about 1:10 and about 10:1.
 12. Themethod of claim 1, wherein the fatty alcohol comprises stearyl alcohol,cetyl alcohol, or both.
 13. The method of claim 1, wherein the fattyalcohol comprises one or more of stearyl alcohol, cetyl alcohol, behenylalcohol, or myristyl alcohol.
 14. The method of claim 1, wherein theminocycline antibiotic is present at about 0.5% to about 6% by weight ofthe carrier.
 15. The method of claim 1, wherein the hydrophobic solventis selected from the group consisting of an alexandria laurel tree oil,an almond oil, an essential oil, an unsaturated or polyunsaturated oil,an apricot stone oil, an avocado oil, a barley oil, a basil oil, aborage seed oil, a calendula oil, a camphor oil, a canelle nut tree oil,a canola oil, a cardamom oil, a carrot oil, a castor oil, a citronellaoil, a clary sage oil, a clove oil, a coconut oil, a cod-liver oil, acorn oil, a cotton oil, a cottonseed oil, a cypress oil, anepoxy-modified silicone oil, an ester oil, an evening primrose oil, afatty acid-modified silicone oil, a flaxseed oil, a fluorogroup-modified silicone oil, a frankincense oil, a ginger oil, a grapeseed oil, a grapefruit oil, a groundnut oil, a hazelnut oil, a heavymineral oil, a hempseed oil, a herring oil, hydrocarbon oils, a hyssopoil, a jasmine oil, a jojoba oil, a lavender oil, a lemon oil, a lightmineral oil, a lucerne oil, a maize germ oil, a maleated soybean oil, amandarin oil, a manuka oil, a marjoram oil, a marrow oil, medium chaintriglyceride (MCT) oil, a millet oil, a mineral oil, a myrrh oil, aneroli oil, a nutmeg oil, oils from animal origin, oils of plant origin,an olive oil, a palm oil, a passionflower oil, a peanut oil, apetitgrain oil, a polyether group-modified silicone oil, a poppy oil, arapeseed oil, a rosehip oil, a rye oil, a safflower oil, a sage oil, asalmon oil, a sesame oil, a silicone oil, a soya oil, a soybean oil, asunflower oil, a sweet almond oil, a sysymbrium oil, a syzigiumaromaticum oil, a tangerine oil, a tea tree oil, unsaturated orpolyunsaturated oils, a vanilla oil, a verbena oil, a walnut oil, awheat germ oil, and a mixture of any two or more thereof.
 16. The methodof claim 1, wherein the hydrophobic solvent comprises (i) a diglyceride,capric/caprylic triglycerides, glycereth triacetate, glyceroltriheptanoate, glyceryl oleate, glyceryl trioctanoate, liquidtriglycerides, or a wheat germ glyceride; (ii) a PPG alkyl ether, aPPG-10 cetyl ether, a PPG-10 oleyl ether, a PPG-11 stearyl ether, aPPG-12 butyl ether, a PPG-14 butyl ether, a PPG-15 butyl ether, a PPG-15stearyl ether, a PPG-16 butyl ether, a PPG-17 butyl ether, a PPG-18butyl ether, a PPG-2 butyl ether, a PPG-2 methyl ether, a PPG-20 butylether, a PPG-20 oleyl ether, a PPG-22 butyl ether, a PPG-23 oleyl ether,a PPG-24 butyl ether, a PPG-26 butyl ether, a PPG-28 cetyl ether, aPPG-3 methyl ether, a PPG-3 myristyl ether, a PPG-30 butyl ether, aPPG-30 cetyl ether, a PPG-30 isocetyl ether, a PPG-30 oleyl ether, aPPG-33 butyl ether, a PPG-37 oleyl ether, a PPG-4 butyl ether, a PPG-4lauryl ether, a PPG-4 myristyl ether, a PPG-40 butyl ether, a PPG-5butyl ether, a PPG-50 cetyl ether, a PPG-50 oleyl ether, a PPG-52 butylether, a PPG-53 butyl ether, a PPG-7 lauryl ether, a PPG-9 butyl ether,or a PPG-9-13 butyl ether; (iii) benzyl laurate, benzyl myristate,benzyl palmitate, bis dimer dilinoleate, butyl myristate, butylstearate, propyl myristate, propylene glycol dicaprate, propylene glycoldicaprylate, propylene glycol myristyl ether acetate, propylene glycolricinoleate, stearyl caprate, stearyl propionate, tocopheryl acetate,tocopheryl linoleate, triisocetyl citrate, decyl oleate, diethylhexyladipate, diethylhexyl malate, diethylhexyl succinate, diisopropyladipate, diisopropyl dimerate, diisopropyl sebacate, diisosteary dimerdilinoleate, diisostearyl fumerate, dioctyl malate, dioctyl sebacate,disopropyl adipate, dodecyl oleate, ester derivatives of lanolic acid,ethylhexyl hydroxystearate, ethylhexyl palmitate, ethylhexylpelargonate, ethylhexyl stearate, hexyl laurate, isoamyl laurate,isocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetylsalicylate, isocetyl stearate, isocetyl stearoyl stearate, isodecyloleate, isododecane, isohexadecane, isohexadecanol, isopropylisostearate, isopropyl lanolate, isopropyl laurate, isopropyl myristate,isopropyl palmitate, isopropyl stearate, isosteary citrate, isostearysalicylate, isosteary tartarate, isostearyl behenate, isostearylerucate, isostearyl glycolate, isostearyl isostearate, isostearyllactate, isostearyl linoleate, isostearyl linolenate, isostearyl malate,isostearyl palmitate, lauryl lactate, myristyl lactate, myristylmyristate, myristyl propionate, neopentylglycol dicaprate,neopentylglycol dicaprylate/dicaprate, octyl palm itate, octyl stearate,octyldodecyl behenate, octyldodecyl hydroxystearate, octyldodecylmyristate, octyldodecyl stearoyl stearate, oleyl erucate, oleyl lactate,oleyl oleate, or pentaerythrityl tetrastearate; (iv) alkyl benzoate,alkyl octanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate,stearyl heptanoate, tridecyl ethyl hexanoate, tridecyl isononanoate, acetearyl ethyl hexanoate, cetearyl isononanoate, cetearyl octanoate,cetyl ethyl hexanoate, cetyl octanoate, diethyleneglycoldiethylhexanoate, diethyleneglycol diisononanoate, diethyleneglycoldioctanoate, diethylhexanoate, ethylhexyl cocoate, ethylhexyl ethylhexanoate, ethylhexyl isononanoate, isocetearyl octanoate, isodecylethylhexanoate, isodecyl isononanoate, isohexyl decanoate, isononylisononanoate, isononyl octanoate, isostearyl isononanoate, isostearylneopentanoate, isotridecyl isononanoate, or myristyl neopentanoate; (v)a caprylyl methicone, cetyl dimethicone, stearyl dimethicone, acyclohexasiloxane, a cyclomethicone, cyclopentasiloxane, acyclotetrasiloxane, dimethicone, dimethyl polysiloxane,methylphenylpolysiloxane, PEG/PPG 18/18 dimethicone, phenyltrimethicone, a poly-diphenyl-siloxane copolymer, a polyalkyl siloxane,a polyalkylaryl siloxane, a polyaryl siloxane, or a polyether siloxanecopolymer; (vi) an acetylated lanolin alcohol, a liquid paraffin,octyldodecanol, a polyalphaolefin, a polyisobutylene, a polyolefin, or asynthetic isoalkane; or (vii) a mixture of any two or more thereof. 17.The method of claim 1, wherein the foamable composition is administeredat least once daily.
 18. The method of claim 1, wherein the foamablecomposition is administered at least once daily and the minocycline ispresent at about 3% by weight of the carrier.
 19. The method of claim 1,wherein the foamable composition is administered at least once daily andthe minocycline is present at about 1.5% by weight of the carrier. 20.The method of claim 1, wherein the foamable composition comprises atleast one fatty alcohol, at least one fatty acid, and at least one wax.21. The method of claim 1, wherein the ratio of fatty alcohol to fattyacid is about 1:7 to about 16:3.
 22. The method of claim 1, wherein theratio of fatty alcohol to fatty acid is about 3:17 to about 2:1.
 23. Themethod of claim 1, wherein the foamable composition is free ofpetrolatum.
 24. The method of claim 1, wherein the salt of minocyclineis minocycline hydrochloride.